key: cord-309795-2kozsv4z
authors: Dewidar, Bedair; Kahl, Sabine; Pafili, Kalliopi; Roden, Michael
title: Metabolic liver disease in diabetes – from mechanisms to clinical trials
date: 2020-06-20
journal: Metabolism
DOI: 10.1016/j.metabol.2020.154299
sha: 
doc_id: 309795
cord_uid: 2kozsv4z

Abstract Non-alcoholic fatty liver disease (NAFLD) comprises fatty liver (steatosis), non-alcoholic steatohepatitis (NASH) and fibrosis/cirrhosis and may lead to end-stage liver failure or hepatocellular carcinoma. NAFLD is tightly associated with the most frequent metabolic disorders, such as obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM). Both multisystem diseases share several common mechanisms. Alterations of tissue communications include excessive lipid and later cytokine release by dysfunctional adipose tissue, intestinal dysbiosis and ectopic fat deposition in skeletal muscle. On the hepatocellular level, this leads to insulin resistance due to abnormal lipid handling and mitochondrial function. Over time, cellular oxidative stress and activation of inflammatory pathways, again supported by multiorgan crosstalk, determine NAFLD progression. Recent studies show that particularly the severe insulin resistant diabetes (SIRD) subgroup (cluster) associates with NAFLD and its accelerated progression and increases the risk of diabetes-related cardiovascular and kidney diseases, underpinning the critical role of insulin resistance. Consequently, lifestyle modification and certain drug classes used to treat T2DM have demonstrated effectiveness for treating NAFLD, but also some novel therapeutic concepts may be beneficial for both NAFLD and T2DM. This review addresses the bidirectional relationship between mechanisms underlying T2DM and NAFLD, the relevance of novel biomarkers for improving the diagnostic modalities and the identification of subgroups at specific risk of disease progression. Also, the role of metabolism-related drugs in NAFLD is discussed in light of the recent clinical trials. Finally, this review highlights some challenges to be addressed by future studies on NAFLD in the context of T2DM.

Nonalcoholic fatty liver diseases (NAFLD) is currently defined by lipid deposition that exceeds more than 5% of hepatocytes, as assessed from liver biopsy, and/or by more than 5 .6% hepatocellular fat content per liver weight, as assessed from magnetic resonance (MR) methods, in the absence of significant alcohol consumption and other causes of fatty liver [1, 2] . NAFLD, which affects about 25% of the population [3] , comprises a broad range of abnormalities ranging from simple fatty liver (steatosis) to non-alcoholic steatohepatitis (NASH), characterized by inflammation, necrosis, and hepatocellular ballooning, and progression to liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) [2] . Some gene variants promote risk of NAFLD by altering lipid droplet formation and de novo lipogenesis (DNL), such as variants of patatin-like phospholipase domain-containing protein 3 (PNPLA3) and glucokinase regulatory protein [4] , or by decreasing very-low-density lipoproteins (VLDL) export as shown for a missense mutation (E167K) in transmembrane 6 superfamily member 2 (TM6SF2) [5] .

Nevertheless, NAFLD is tightly associated with common acquired metabolic diseases such as obesity and type 2 diabetes (T2DM). The mutual relationship between both diseases is illustrated by several epidemiological data. The prevalence of steatosis and NASH has been estimated to be 50 and 56%, respectively, in T2DM [6] . The age-adjusted relative risk of NAFLD is about 5.36fold higher in T2DM compared to healthy humans [7] . T2DM is also an emerging risk factor for NASH progression to advanced fibrosis, cirrhosis and HCC [8, 9] .

Diabetes was even a better predictor for HCC development in people with NASH and cirrhosis compared to other metabolic risk factors such as hyperlipidemia, body mass index (BMI) and hypertension [10] . Recently, a consensus panel has proposed to rename NAFLD a metabolic-dysfunction-associated fatty liver disease (MAFLD) based on the presence of overweight/obesity, T2DM and evidence of so-called "metabolic dysregulation" [11] . Future will tell, if this will help to better understand the multiple relationships between NAFLD and T2DM. In this context, NAFLD per se associates with more than double risk of incident diabetes pointing to specific liver-related mechanisms [12, 13] . Moreover, multicenter studies in Skandinavia and Germany have recently found that diabetes can be stratified into subtypes J o u r n a l P r e -p r o o f the circulation. On the contrary, a recent study demonstrated that obesity-induced insulin resistance preceded inflammation in adipose tissues of mice [29] . Indeed, adipose tissue inflammation might be a protective feedback mechanism as its local inhibition in mice induced ectopic lipid accumulation in liver, glucose intolerance, and systemic inflammation [30] .

Besides released inflammatory cytokines and FFA, adipose tissue could still communicate with the liver and muscle through secretion of different adipokines such as adiponectin and leptin. Persons with NASH have lower serum adiponectin compared to those with NAFLD with or without normal liver enzymes [31] . By contrast, the circulating levels of leptin were higher in people with NAFLD and T2DM, probably due to increased leptin resistance, and were associated with disease severity [32] .

Increased FFA influx to skeletal muscle promotes accumulation of intramyocellular lipid (IMCL). Reduced mitochondrial oxidation contributes as well to IMCL as shown in aging and insulin-resistant humans [33] . Consequently, skeletal muscle exhibits insulin resistance, which often precedes the onset of T2DM and insulin resistance in the liver [34] . Lipid intermediate metabolites, in particular sn 1,2 diacylglycerols (DAG), link IMCL to skeletal muscle insulin resistance through activation of protein kinase C-theta (PKCθ) resulting in its translocation from cytoplasm to the plasma membrane [35] . Muscles of insulin resistant humans with obesity and T2DM showed increased DAG content and PKCθ activity as compared to healthy humans [35] . Mutation studies highlighted serine amino acid residue (Ser1101) of IRS1 to be a substrate for activated PKCθ [36] . As a consequence of skeletal muscle insulin resistance, postprandial energy storage shifts from glycogen synthesis in the muscle into triacylglycerol (TAG) in the liver, promoting NAFLD development [25] .

Gut microbiome is increasingly recognized as a modulator of liver pathogenesis through what is called the "gut-liver axis" [37] . Distinctive alterations of gut microbiome were reported in humans having NASH and T2DM [38] . The intestinal microbiome alters host metabolism by modulating the production of short-chain fatty acids (SCFA) e.g. butyrate, acetate, and propionate, which have beneficial effects on insulin sensitivity, lipid and glucose metabolism [38] . Also, intestinal dysbiosis could associate with increased intestinal permeability permitting translocation of bacterial lipopolysaccharide (LPS) into the systemic circulation, J o u r n a l P r e -p r o o f 6 which could induce fat deposition in the liver, NASH progression, weight gain, and diabetes [39] . Moreover, intestinal microbiome could suppress the expression of fasting-induced adipocyte factor (FIAF) in intestinal epithelium, which functions as an inhibitor of circulating lipoprotein lipase, resulting in increased TAG storage in the peripheral tissues [22] . Also, ethanol-producing microbiome could increase blood alcohol concentration in NASH, which is metabolized in the liver generating high levels of reactive oxygen species (ROS). The last mechanism could explain the histological similarity between NASH and alcoholic steatohepatitis [22] . Furthermore, microbiota metabolize liver-derived primary bile acids into secondary bile acids. The latter are reabsorbed into bloodstream and may act as signaling molecules via a variety of receptors including farnesoid X receptor (FXR), which regulates the transcription of different metabolic genes involved in bile acid synthesis, transport, lipogenesis, and glucose homeostasis [40] .

Insulin resistance in both skeletal muscle and adipose tissues initiates liver steatosis by providing precursors and substrates for DNL and mitochondrial β-oxidation e.g. glucose, FFA and glycerol [25] . Although reesterification of FFA derived from diet and adipose tissue is the dominant contributor to TAG pool in the liver (59%), it did not increase in people with NAFLD. On the other side, DNL-derived FFA contribute by about 26%, which is severalfold higher as compared to individuals without NAFLD (10%) [41] .

Later, insulin resistance of the liver develops, resulting in increased gluconeogenesis and elevation of endogenous glucose production (EGP) from the liver, which contributes to fasting hyperglycemia in individuals with T2DM [25] . Insulin signaling inhibits typically hepatic gluconeogenesis through Akt-induced phosphorylation of forkhead box (FOXO1) and induces lipogenesis through activation of sterol regulatory element-binding proteins (SREBP1C) and mammalian target of rapamycin complex (mTORC1) pathways. During hepatic insulin resistance, insulin does not suppress gluconeogenesis efficiently, while DNL is preserved or even increased. To explain this discrepancy, pathway-selective hepatic insulin resistance was postulated, which means that only one arm of insulin signaling is defective i.e.

Akt/FOXO1 leading to reduced insulin-mediated suppression of gluconeogenesis, whereas insulin-activated SREBP-1C/mTORC1 pathway remains intact and activates lipogenesis [28] .

Actually, DNL was reduced after induction of hepatic insulin resistance by feeding mice with J o u r n a l P r e -p r o o f 7 a high-fat diet (HFD) [42] , which challenges the concept of selective hepatic insulin resistance and suggest the existence of alternate mechanisms that contribute to increased DNL and gluconeogenesis in insulin-resistant liver, for example, hyperinsulinemia, insulinindependent re-esterification of adipose tissue-derived FFA, and increased acetyl CoA generation from β-oxidation of FFA, which allosterically activates pyruvate carboxylase enzyme, leading to enhanced gluconeogenesis [25] . In addition, increased blood glucose level can activate carbohydrate response element-binding protein (ChREBP) signaling pathway, thereby stimulating expression of several glycolytic genes, which provide additional metabolic precursors for DNL [43] . In line, ChREBP overexpression induced stearoyl-CoA desaturase 1 (Scd1) expression, an enzyme responsible for the biosynthesis of monounsaturated fatty acids (MUFA), resulting in increased liver fat content [44] .

PKC epsilon (PKCε) is crucial in mediating hepatic insulin resistance and once activated by DAG, it translocates to the cell membrane, and phosphorylates specific threonine residue (Thr1160 in human and Thr1150 in mouse) on insulin receptor leading to destabilization of the active configuration of insulin receptor kinase and inhibition of its tyrosine kinase activity [45] (Figure 2 ). In general, both hyperglycemia and toxic lipids such as ceramides, DAG, FFA, and cholesterol can induce deleterious effects on liver cells (glucolipotoxicity), which might initiate NAFLD progression from simple steatosis to NASH and fibrosis via various mechanisms, including cell death, oxidative stress, endoplasmic reticulum (ER) stress and mitochondrial disorders [46] .

Alterations in the activity and abundance of oxidative phosphorylation (OXPHOS) proteins and antioxidant enzymes were described in various animal models of NAFLD [47] . Impaired hepatic mitochondrial function was evident as well in T2DM and NASH [48, 49] . In a mouse model of choline-deficient diet-induced NAFLD, mitochondrial OXPHOS was increased at 12 weeks but lost at a later time point [50] . Also, the higher maximal respiration rate of liver mitochondria was severalfold higher in insulin-resistant obese individuals with fatty liver as compared to lean individuals [51] . These studies highlight the flexibility of mitochondria to adapt to increased metabolic inputs to keep energy homeostasis and to protect against the harmful effects of increased FFA and TAG in the liver. In NASH, mitochondrial flexibility was lost, which was associated with increased ROS production and exhaustion of protective antioxidant enzymes [51] (Figure 2 ). Whether loss of mitochondrial flexibility is a cause or consequence for NAFLD progression remains obscure. Depletion of ATP due to J o u r n a l P r e -p r o o f mitochondrial disorders, together with hyperglycemia and lipid overload could be inducers for another signaling pathway, termed unfolded protein response "UPR", which is adaptive response to resolve unfolded or misfolded proteins and to restore ER homeostasis [52, 53] .

Prolonged UPR stress can activate JNK and NF-kB signaling pathways, which are involved in insulin resistance, liver steatosis, and inflammation [52] . Furthermore, ER stress could increase insulin resistance through induction of lipin-2 expression, which is a phosphatase enzyme that catalyzes biosynthesis of DAG leading to activation of DAG/PKCε axis [54] .

Interestingly, UPR could also increase liver steatosis through activation of SREBP-1c signaling pathway [53] .

Elevated ROS and UPR are well-identified pathways that could induce hepatocytes death in NASH. Hepatocytes apoptosis and necroptosis are the main forms of cell death in human steatohepatitis and diet-induced mouse models of NASH [55] . The key fibrogenic liver cells, hepatic stellate cells (HSCs), usually exist in a quiescent state and get activated by engulfment of apoptotic bodies, the inflammatory milieu, or damage-associated molecular patterns (DAMPs) released from stressed and dying hepatocytes [56] . Interestingly, FFA-mediated lipotoxic effects stimulate hepatocytes to release extracellular vesicles (EVs) with distinctive microRNAs (miRNA) profile that increase the expression of fibrogenic genes in the surrounding HSCs [57] (Figure 3 ). Free cholesterol could directly sensitize HSCs to the action of tumor growth factor (TGF)-β, a potent fibrogenic cytokine [58] . Treatment of human and rat immortalized HSCs cell lines with saturated fatty acid increased the expression of various profibrogenic genes [59] . Macrophages aggregate as well around dead hepatocytes forming a crown-like structure, a phenomenon that exists only in persons with NASH but not in those with simple steatosis [60] . Recruitment of more inflammatory cells from systemic circulation is facilitated by "Find me" signals that are released from dead cells [61] . Inhibition of inflammatory monocytes recruitment via inhibition of C-C chemokine receptors type 2 and type 5 (CCR2/CCR5) suppressed fibrogenesis and steatohepatitis in murine NASH [62] .

Macrophages can modulate also hepatic insulin resistance and favor TAG accumulation in hepatocytes through secretion of IL-1β that downregulates peroxisome proliferator-activated receptor (PPAR) α, a key transcriptional pathway involved in fatty acid oxidation [63] . Liver sinusoidal cells (LSECs) are fenestrated cells that exist in close vicinity to hepatocytes, J o u r n a l P r e -p r o o f macrophages and HSCs, which, under physiological conditions, regulate lipid transport, maintain the quiescence of Kupffer cells, resident liver macrophages, and HSCs [64] . At early stage of NAFLD, LSECs lose their fenestrae, a process termed capillarization, which could favor liver steatosis and initiate HSCs activation [64] (Figure 3 ). During NASH, LSECs display a pro-inflammatory phenotype that promotes steatohepatitis [64] .

Autophagy is a self-degradative process which is used by the cells to remove misfolded proteins and damaged organelles [65] . Singh et al. showed that the cells can use autophagic process as lipolytic mechanism to mobilize lipids from intracellular lipid store, which is termed in this case "macrolipophagy" [66] . Various in vitro and in vivo studies showed that autophagy was decreased in fatty hepatocytes [67] . Impairment of autophagy by palmitic acid in macrophages induces inflammatory IL-1β production [68] . On the other side, selective loss of autophagic activity reduced liver fibrogenesis in cultured HSCs [69] and protected against diet-induced insulin resistance [70] . The results highlight that the net effect of autophagy on NAFLD might depend on the tissue or type of the cells that show autophagic dysfunction and the stage of NAFLD.

The liver biopsy is considered the gold standard for NAFLD diagnosis, especially for distinguishing steatosis from inflammation and fibrosis [2] . Nevertheless, this technique has several limitations not only resulting from the invasive procedure and rare post-interventional complications, but also due to the small tissue volume, which might not be representative for the whole liver and may not take into account inhomogeneous distribution of NAFLDassociated alterations. Novel imaging modalities such as ultrasound-or MR-based techniques are of increasing value, as recently reviewed [71] , but are still not generally available, so that there is an urgent need for noninvasive screening tools.

Non-invasive detection of NASH and fibrosis remains challenging today. Biomarker-based panels such as aspartate aminotransferase (AST)/platelets count ratio index, fibrosis-4 (FIB-4) index, FibroTest, FibroSpect II, and NAFLD fibrosis score (NFS) offer variable diagnostic efficacy for assessing different stages of liver fibrosis [73, 74] . Although combination of these panels could enhance their predictive values [73] , they still suffer from limited accuracy even compared to the alanine aminotransferase (ALT) and AST, particularly in T2DM [75] . In this regard, transient elastography looks like a promising alternative in diabetes clinics for detection of liver fibrosis in NAFLD [74] .

Numerous biomarkers have been developed to specifically track features of NASH progression and fibrosis. Cytokeratin (CK) 18, an intermediate filament protein that is cleaved during cell death to CK18 M30 and CK18 M65, has been intensively investigated as a surrogate of NASH-associated liver cell damage, but a recent meta-analysis of 25 studies reported a maximum sensitivity of 0.75 for NASH diagnosis [76] and suboptimal diagnostic value was shown in T2DM [75] . The ECM turnover marker, type III procollagen, can offer a diagnostic efficacy of 0.81 and 0.88 to detect moderate and advanced liver fibrosis in T2DM, respectively [77] .

In 2016, the European Associations for the Study of the Liver, Obesity and Diabetes (EASL-EASO-EASD) jointly released recommendations for diagnosis and monitoring of disease severity in persons with suspected NAFLD and metabolic risk factors [78] . People with metabolic risk factors, such as T2DM, should undergo assessment by abdominal ultrasound, serum transaminases and fibrosis markers (e. g. FIB-4, NFS). Elevated transaminases or steatosis plus abnormal fibrosis test shall require referral to a specialist. This strategy has raised the question of a possible overreferral when adhering to these guidelines [79] .

However, recent analyses show that a refined strategy of specific combining indices such as FLI and FIB-4 could reduce the number of people with T2DM for further diagnostic work up to a reasonable size [80] . This retrospective analysis also found that certain non-invasive biomarkers are consistently associated with different patterns of diabetes-related complications.

Analyses of the plasma metabolomic of insulin-resistant individuals with NAFLD suggested that bile salts, e. g. glycocholate, taurocholate, and glycochenodeoxycholate allow to detect NASH in one study [81] , while another study reported an association with insulin resistance J o u r n a l P r e -p r o o f but not with liver necroinflammation [82] . Also amino acids, specifically a glutamate-serineglycine index, was associated with hepatic insulin resistance and transaminases and discriminated individuals with fibrosis grade 3-4 from those with grade 0-2 independently of BMI [83] . The diagnostic performance of a serum-based lipidomic analysis was substantially lower for NAFLD detection in T2DM compared to healthy individuals [84] . Nevertheless, certain sphingolipid species were recently found to be increased in insulin-resistant NASH and to correlate with hepatic oxidative stress and inflammation [85] .

One circulating small noncoding RNA, miRNA-122, was found to be more than 5.7fold in steatosis and further doubled in NASH [86] . This miRNA was also higher in T2DM with NAFLD than in those without NAFLD and provided better prediction of NAFLD when combined with LDL and waist-to-hip ratio [87] . Moreover, extracellular vesicles (EV), which among other cargo also transport miRNA, may be promising biomarkers for NAFLD as shown by higher serum levels in people with NAFLD, obesity and diabetes [107] .

Recently, metagenomics data derived from gut microbiota alterations allowed to detect advanced fibrosis in 86 NAFLD patients, of whom 23% had T2DM, with a robust diagnostic accuracy (AUROC: 0.936) [88] .

The current guidelines recommend only lifestyle modification and -for certain groupsbariatric or metabolic surgery to treat NAFLD [1, 2] . Although the numerous activities in this field, no pharmacological treatment is currently approved or expecting approval for the use in NAFLD with or without concomitant T2DM (Table 1 and 2), except for obeticholic acid (OCA). Marketing authorization application for OCA has been submitted to the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA), awaiting FDA decision by June 2020 [89] . Against this background, current guidelines and recommendations primarily advise lifestyle modification (healthy nutrition and exercise) and weight loss in overweight/obese persons. The EASL-EASO-EASD guidelines recommend to consider pharmacological treatment in people with NASH when combined with fibrosis and in those with less severe disease, but high risk conditions for disease progression such as T2DM [78] . The American Association for the Study of Liver Diseases (AASLD) recommends to limit pharmacological treatment to those with biopsy-proven NASH and fibrosis [1] .

J o u r n a l P r e -p r o o f

Weight management and physical exercise are key to the treatment of both NAFLD and T2DM. A proof-of-concept study showed that a hypocaloric diet with weight loss of ~8 kg within 12 weeks not only normalized fasting EGP and thereby hyperglycemia, but decreased hepatic TAG content down to normal concentrations in obese T2DM humans with NAFLD [90] . Subsequent studies in larger cohorts extended these results by demonstrating that a very low-caloric diet with weight loss of about 15% rapidly normalized liver fat content in 90 in dividuals with T2DM, which persisted for one year if weight loss was maintained [91] .

Interestingly, Mediterranean, low-saturated fat and high plant-based protein diets also improve steatosis in NAFLD combined with T2DM despite minor or no relevant weight loss [92, 93] . In addition, physical activity and exercise training interventions can also decrease liver fat content, which may not be exclusively depending on concomitant weight loss [94] .

Although the beneficial effects of structured behavioral treatment to improve histological endpoints, likely extend beyond reduction of hepatic fat content to ameliorating the grade and stage of inflammation and fibrosis [95] , only a minority of the people manages to adhere to dietary weight loss and exercise programs, which raises the issue of other therapeutic approaches [94] .

Weight-loss inducing drugs could be an attractive option for persons with NAFLD with a BMI > 30 kg/m 2 or >27 kg/m 2 in the presence of at least one metabolic comorbidity, as an adjunct treatment to lifestyle modifications [96, 97] . Currently, the most-popular weight-loss inducing medications associated with at least 5% body weight decrease in one year as compared to placebo are orlistat, the fixed combination of phentermine and topiramate or naltrexone and bupropion, and the glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1ra), liraglutide [97] . Of these drugs, orlistat treatment failed to improve liver histology when compared to placebo [98] , while no reports are available for topiramate, naltrexone, bupropion and phentermine regarding hepatic endpoints in humans with NAFLD [99] . Only Bariatric or metabolic surgery is a therapeutic option to induce sustained weight loss partricularly in people with combined NAFLD and T2DM. In obese humans, bariatric surgery resulted in 85% resolution of NASH within one year [101] and in 77% complete remission of T2DM [102] . Surgical weight loss improves glucose metabolism and insulin sensitivity by different mechanisms such as increased GLP-1 secretion [103] and epigenetic modification [104, 105] .

Several antihyperglycemic drug classes were or are currently being investigated in clinical trials and preclinical models to evaluate their efficacy for people with NAFLD and with or without T2DM.

Metformin reduces body weight, hepatic gluconeogenesis -by yet unclear mechanisms [106] , and the risk of macrovascular complications, which is still controversially discussed due to lack of optimally designed clinical trials [116] . Despite its action on hepatic metabolism, former small-scale studies reported conflicting results [109, 110] (Table 1 ) and recent metaanalysis failed to demonstrate any effect of metformin on liver histology [111] .

Nevertheless, epidemiological, observational and preclinical studies suggest that metformin may reduce the risk of HCC and also in T2DM, possibly by promoting apoptosis, but controlled clinical trials are not available [112] .

DPP4 degrades incretins such as GLP-1 so that DPP-4i treatment increases the postprandial levels of endogenous GLP-1, which leads to lower glucose peaks after meals [113, 114] . In individuals with NAFLD with prediabetes or recent onset diabetes, sitagliptin did not improve liver steatosis or liver fibrosis compared to placebo as assessed by MR-based techniques [115] . In line, another recent trial reported no benefits for sitagliptin versus placebo on liver fibrosis or steatohepatitis in T2DM [116] (Table 1) . In contrast, a moderate reduction in liver fat content was observed with vildagliptin in individuals with T2DM [117] .

J o u r n a l P r e -p r o o f 14 The actions of endogenous GLP-1 are mimicked by GLP-1 receptor agonists (GLP-1ra), which effectively reduce blood glucose levels and also reduce the risk for CVD in T2DM [118] . In individuals with NAFLD and T2DM, liraglutide in combination with metformin reduced liver, subcutaneous, and visceral fat [119] . Also, liraglutide improved hepatic steatosis measured by MR-based methods as well as resolved biopsy-proven NASH without worsening of fibrosis [100, 120] (Table 1) . However, a recent subanalysis did not detect an effect of liraglutide on liver fat content quantified by 1 H-MRS [121] (Table 1) . Respective trials with semaglutide and dulaglutide are still waiting for results (NCT02970942, NCT03648554). In an animal model of T2DM, exenatide also counteracted HCC development by suppression of STAT3-regulated genes [122] .

Glucose-dependent insulinotropic polypeptide (GIP) represents the second important incretin with proposed beneficial effects on peripheral energy metabolism [123] . Tirzepatide, a novel dual agonist for GIP and GLP-1 receptors with probably greater efficacy than GLP-1ra [124] , decreased transaminases and surrogate markers of liver injury paralleled by increased circulating adiponectin levels in people with T2DM [125] . A clinical trial on NASH resolution is currently ongoing in persons with NASH with or without T2DM (NCT04166773).

SGLT2i inhibit reabsorption of glucose in the proximal renal tubule resulting in glucosuria and calory loss, thus effectively reducing blood glucose level and body weight in T2DM.

Moreover, SGLT2is show beneficial effects on cardiovascular risk and progression of nephropathy [118, 126] . Most, but not all recent randomized controlled trials (RCTs) showed that SGLT2i treatment resulted in reduction in liver fat content compared to placebo [127] [128] [129] [130] [131] (Table 1) . In an open-label pilot study in liver-biopsy proven cohort of NASH with T2DM, treatment with empagliflozin for 6 months reduced liver steatosis, ballooning and fibrosis and induced NASH resolution in approximately half of those persons [132] . Animal models further suggested anti-inflammatory, anti-oxidant and pro-apoptotic actions of SGLT2i with cardio-protective effects as well as inhibition of NASH progression and tumor growth of HCC [133, 134] . The dual SGLT1/2i, licogliflozin, is expected to block both intestinal and renal glucose (re)absorption [135] and currently investigated to evaluate its efficacy on resolution of NASH as monotherapy and as combination therapy with the FXR agonist, tropifexor, in people with NASH and fibrosis (NCT04065841). First results hint at improvement of transaminases and reduction of steatosis by licogliflozin in NASH [136] .

PPARs is a family of nuclear receptors composed of multiple isoforms with wide tissue distribution [137] . The PPAR-γ agonist pioglitazone had convincing efficacy on NASH resolution in individuals with and without T2DM, but with conflicting results on fibrosis [138] [139] [140] (Table 1) . Of note, pioglitazone has been withdrawn in many European countries because of its disadvantageous safety profile [231] . However, pioglitazone exerts beneficial effects on cardiovascular outcomes in persons with T2DM and a history of CVD [141] .

It has been proposed that non-PPAR-γ dependent mechanisms, as the inhibition of the mitochondrial pyruvate carrier (MPC), might mediate the beneficial effects of pioglitazone on NAFLD [142] . However, a novel drug with PPAR-γ sparing effects and MPC binding activity did not improve histological components of NASH in individuals with T2DM compared to placebo [143] .

Elafibranor is a dual agonist for PPAR-α and PPAR-δ without PPAR-γ stimulation [144] .

Based on a post-hoc analysis, NASH was resolved without worsening of fibrosis in a higher percentage of people with and without T2DM in the elafibranor group as compared to the placebo [145] and a follow-up study on these findings has been initiated ( Table 2) . Recent announcements on an interim analysis state that elafibranor treatment failed to resolve NASH and improve fibrosis when compared to placebo [146] .

Saroglitazar is another dual PPAR-α/γ agonist with higher affinity for PPAR-α. In a mouse model of NASH, saroglitazar reduced liver steatosis, inflammation and prevented fibrosis development and a respective clinical trial is ongoing [147] ( Table 2) . Lanifibranor is a pan-PPAR agonist for PPAR-α, β, and γ receptors focused on treatment of liver fibrosis and NASH (NCT03008070). In an animal model of liver fibrosis, lanifibranor decreased hepatic collagen deposition [148] .

Several other strategies for pharmacological targeting of NASH have emerged over the last few years; however, these strategies are not specifically designed for T2DM, but for the whole NAFLD collective. They comprise antiinflammatory drugs, but also modulators of other pathways, which are briefly summarized in the following sections.

J o u r n a l P r e -p r o o f FXR can be activated by bile acids in a negative feedback mechanism to suppress bile acid synthesis [40] . OCA is a potent semisynthetic and selective FXR agonist approved for treatment of primary biliary cholangitis [149] . OCA treatment resulted in histologic improvement of NASH in people with and without T2DM compared to placebo [150, 151] ; however, concerns were raised about OCA-induced changes in plasma lipoprotein profile [152] . Tropifexor, another potent FXR agonist [153] , is currently being tested in combinatorial approaches of NASH treatment (cenicriviroc and licogliflozin; NCT03517540).

Oltipraz is a synthetic dithiolethione with antisteatotic effects by inhibiting the activity of LXR-α. It activates adenosine monophosphate activated protein kinase (AMPK) and

inactivates S6K1, affecting LXR-α thus reducing lipogenesis and increasing lipid oxidation [154] . A recent 24-week phase 2 clinical trial found decreased steatosis measured by 1 H-MRS with oltipraz compared to placebo treatment [154] and a respective phase 3 clinical trial is ongoing ( Table 2 ).

Chemokine receptors type 2 (CCR2) and type 5 (CCR5) are expressed on various inflammatory and fibrogenic cells [155] . Cenicriviroc is a CCR2/CRR5 dual antagonist that reduced insulin resistance, liver inflammation and fibrosis in diet-induced models of NASH [62] . In recent RCTs in a NASH cohort with fibrosis, cenicriviroc treatment did not improve NAS but may reduce liver fibrosis [156, 157] . Currently, there is an ongoing clinical trial to evaluate the effects of cenicriviroc on fibrosis in NASH ( Table 2) .

Both people with obesity, metabolic syndrome or T2DM as well as those with NAFLD are at increased risk for dyslipidemia. Statins, inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, are generally safe and have unmet efficacy to decreased serum LDL and prevent cardiovascular outcomes, despite slightly increasing the risk of T2DM [2] .

Use of statins associated with a 46% lower relative risk of hepatic decompensation and mortality in cirrhosis and a trend towards lower fibrosis progression in non-cirrhotic liver diseases [158] . However, the data on liver histology ist limited [159] so that statins are not currently recommended for the management of NAFLD [2] . The inhibitor of intestinal J o u r n a l P r e -p r o o f cholesterol absorption, ezetimibe, decreased the histological NAS, but not consistently liver fat content in an analysis of the few available studies [160] . Fenofibrate, a PPAR-α agonist, does not affect or even increase liver fat content or volume [161, 162] . Nevertheless, the combination of statins with certain anti-NASH drugs, such as OCA, could be beneficial to counteract drug-related increases in LDL during long-term treatment.

Inhibition of DNL in NAFLD may be achieved by inhibition of ACC as this enzyme catalyzes the conversion of acetyl CoA into malonyl CoA, which acts as a substrate for fatty acid synthesis and inhibitor for fatty acid β-oxidation [163] . In a recent clinical trial in individuals with NASH with and without T2DM, treatment with the dual ACC1 and ACC2 inhibitor GS-0976 decreased liver steatosis without improvement of fibrosis [164] . The major concern of this strategy is that decreased DNL in NAFLD might channel lipids towards other harmful directions, e.g. increased blood lipids [163] .

SCD1 is a key enzyme for hepatic lipogenesis that catalyzes the conversion of saturated fatty acids to MUFA and its downregulation protected mice from high carbohydrate-induced liver steatosis [165] . A clinical trial with aramchol, an inhibitor of SCD1, showed a reduction in liver fat content, resolution of NASH and improvement of liver fibrosis in persons with NAFLD with prediabetes or T2DM [166] . These results paved the way for a respective phase 3 clinical trial ( Table 2) .

Mitochondrial uncoupling describes any process that uncouples the electron transport from ATP synthesis in mitochondria [167] . 2,4-dinitrophenol (DNP) was widely used for the treatment of obesity before its discontinuation due to life-threatening serious adverse events [168] . To overcome the side effects of DNP, improved formulas of DNP were recently developed to decrease the toxic to effective dose ratio (DNP-methyl ether (DNPME) and controlled-release mitochondrial protonophore (CRMP)) [169, 170] . Oral CRMP targets mainly the liver due to the first-pass effect and decreased hepatic insulin resistance, hepatic steatosis and liver fibrosis in a methionine-choline deficient rat model of NASH [170] . CRMP was also effective in nonhuman primates with diet-induced NAFLD for reduction of hepatic steatosis and EGP [171] .

Thyroid hormone deficiency has been associated with NAFLD development [172] . Thyroid hormone analogues decreased liver fat, liver transaminases, and inflammatory and fibrosis markers in animal models of NASH [172] . Resmetirom is a liver-targeted highly selective THR-β agonist which showed efficacy in reducing liver fat content in NASH with and without T2DM [173] . Currently, there is ongoing clinical trial for evaluation of long-term outcomes of resmetirom and its efficacy on NASH resolution ( Table 2 ).

Vitamin E is a potent antioxidant [174] . In NASH without T2DM, vitamin E improved NAS without worsening of fibrosis [139] . Despite concerns regarding adverse effects of long term vitamin E usage, treatment with vitamin E for ≥2 years reduced the risk of liver failure in a NASH cohort with advanced fibrosis and with or without T2DM [175] .

Therapeutic manipulation of intestinal microbiome is still in its infancy. Rodent data showed efficacy for fecal microbiota transplantation in improving NAFLD in a diet-induced NASH model [176] . Also, modulation of the intestinal microbiota by antibiotic treatment reduced liver transaminases in NAFLD [177] . The use of prebiotics and probiotics in obese NAFLD/NASH is currently not supported by high-quality clinical studies with MR-or biopsy-based endpoints [178].

The evidence for shared pathophysiological mechanisms between T2DM and NAFLD will help to develop strategies for detecting and treating both diseases and preventing their leading complication, CVD. Altered lipid and energy metabolism, insulin resistance, low-grade inflammation and intestinal dysbiosis represent key targets. In addition to weight loss by lifestyle modification or bariatric surgery, GLP-1ra and SGLT2i are promising antihyperglycemic concepts with beneficial effects on NAFLD and CVD. In addition, many J o u r n a l P r e -p r o o f metabolism-based drugs are currently studied comprising PPAR agonists, endocrine dual coagonists to modulators of hepatic metabolism or microbiota.

Nevertheless, several roadblocks need to be overcome to reduce the burden of NAFLD in T2DM. First, there is still lack of preclinical animal models that encapsulate essential features of human NASH and diabetes. Second, available biomarkers lack diagnostic efficacy to identify NAFLD progression. Innovative strategies such as cluster analysis already enabled detection of a diabetes subtype (SIRD) with high risk of NAFLD [14] . Combination with computational integration of multiomics data shall identify specific disease signatures and pave the way to precision medicine and targeted management of T2DM and NAFLD. Finally, studies on so-called endpoints are scarce, which may be due to the need of long-term studies to evaluate liver-related mortality, to the current neglect to accept CVD morbidity and mortality as NAFLD outcome and to ongoing discussions on the relevance of surrogate markers.

The research of the authors is supported in part by grants from the German Federal Ministry Phase III registered interventional trials on "clinicaltrials.gov" for NAFLD as accessed on 10 th April 2020. BL, baseline; CCR2/5, C-C chemokine receptors type 2 and type 5; FXR, farnesoid X receptor; HbA 1c , glycated haemoglobin; LXR, Liver X receptor; MPC, mitochondrial pyruvate carrier; NA, data not available; NAFLD, non-alcoholic fatty liver disease; NFS, NAFLD fibrosis score; PPAR, peroxisome proliferator-activated receptor; NASH, non-alcoholic steatohepatitis; SCD, stearoyl-CoA desaturase; SGLT, sodium-glucose cotransporter; THR, thyroid hormone receptor; T2DM, type 2 diabetes.

*Only placebo-controlled, randomized clinical trials are listed, except for saroglitazar, a 4-arm active-controlled study. 

The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases

EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease

Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes

Exomewide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease

High Prevalence of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes Mellitus and Normal Plasma Aminotransferase Levels

Type 2 diabetes and risk of hospital admission or death for chronic liver diseases

Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts

Presence of diabetes mellitus and steatosis is associated with liver stiffness in a general population: The Rotterdam study

Diabetes Is Associated With Increased Risk of Hepatocellular Carcinoma in Patients With Cirrhosis From Nonalcoholic Fatty Liver Disease

A new definition for metabolic associated fatty liver disease: an international expert consensus statement

Nonalcoholic Fatty Liver Disease and Risk of Incident Type 2 Diabetes: A Meta-analysis

NAFLD: a multisystem disease

Risk of diabetesassociated diseases in subgroups of patients with recent-onset diabetes: a 5-year follow-up study

Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables

Components of metabolic syndrome are independent predictors of mortality in patients with chronic liver disease: a population-based study

Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus

Is NAFLD Not a Risk Factor for Cardiovascular Disease: Not Yet Time for a Change of Heart

NAFLD and diabetes mellitus

From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options

Non-alcoholic Fatty Liver Disease. The Liver

The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)

Role of diet and lifestyle changes in nonalcoholic fatty liver disease

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance

The integrative biology of type 2 diabetes

Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance

Anti-inflammatory effects of excessive weight loss: potent suppression of adipose interleukin 6 and tumour necrosis factor alpha expression

Potential Nexus of Non-alcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: Insulin Resistance Between Hepatic and Peripheral Tissues

Insulin resistance causes inflammation in adipose tissue

Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling

Serum adiponectin levels in different types of non alcoholic liver disease. Correlation with steatosis, necroinflammation and fibrosis

Serum leptin and leptin resistance correlations with NAFLD in patients with type 2 diabetes

Non-alcoholic Fatty Liver Disease and Insulin Resistance. The Liver

Decreased muscle glucose transport/phosphorylation is an early defect in the pathogenesis of non -insulindependent diabetes mellitus

Role of diacylglycerol activation of PKCθ in lipid-induced muscle insulin resistance in humans

Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101)

The gut-liver axis and the intersection with the microbiome

Gut microbial metabolites in obesity, NAFLD and T2DM

Intestinal microbiota and nonalcoholic steatohepatitis

Update on FXR Biology: Promising Therapeutic Target?

Role of Dietary Fructose and Hepatic de novo Lipogenesis in Fatty Liver Disease

Evidence against Pathway -Selective Hepatic Insulin Resistance in Mice

Mechanisms of Disease: hepatic steatosis in type 2 diabetes--pathogenesis and clinical relevance

The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans

Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance

Molecular Mechanisms of Lipotoxici ty and Glucotoxicity in Nonalcoholic Fatty Liver Disease

Mitochondria in non-alcoholic fatty liver disease

Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis

Liver ATP synthesis is lower and relates to insulin sensitivity in patients with type 2 diabetes

Differential alterations in mitochondrial function induced by a choline-deficient diet: understanding fatty liver disease progression

Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis

Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease

Endoplasmic reticulum stress and the unfolded protein response

Endoplasmic reticulum stress promotes LIPIN2-dependent hepatic insulin resistance

To die or not to die: death signaling in nonalcoholic fatty liver disease

Cell Death and Cell Death Responses in Liver Disease: Mechanisms and Clinical Relevance

Exosomes derived from palmitic acid-treated hepatocytes induce fibrotic activation of hepatic stellate cells

A high-cholesterol diet exacerbates liver fibrosis in mice via accumulation of free cholesterol in hepatic stellate cells

Palmitic acid elicits hepatic stellate cell activation through inflammasomes and hedgehog signaling

Hepatic cholesterol crystals and crown-like structures distinguish NASH from simple steatosis

Mechanisms of Fibrosis Development in NASH

Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis

Macrophages in obesity and non-alcoholic fatty liver disease: Crosstalk with metabolism

Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease

Autophagy: cellular and molecular mechanisms

Autophagy regulates lipid metabolism

Autophagy in non-alcoholic fatty liver disease and alcoholic liver disease

Macrophage-Specific Hypoxia-Inducible Factor-1α Contributes to Impaired Autophagic Flux in Nonalcoholic Steatohepatitis

Autophagy Releases Lipid That Promotes Fibrogenesis by Activated Hepatic Stellate Cells in Mice and in Human Tissues

Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine

Noninvasive imaging methods to determine severity of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

Comparison of liver fat indices for the diagnosis of hepatic steatosis and insulin resistance

The Epidemiology, Risk Profiling and Diagnostic Challenges of Nonalcoholic Fatty Liver Disease

Non-invasive tests for liver fibrosis in NAFLD: Creating pathways between pri mary healthcare and liver clinics

Performance of Plasma Biomarkers and Diagnostic Panels for Nonalcoholic Steatohepatitis and Advanced Fibrosis in Patients With Type 2 Diabetes

Diagnostic Value of CK-18, FGF-21, and Related Biomarker Panel in Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis

Use of Plasma Fragments of Propeptides of Type III, V, and VI Procollagen for the Detection of Liver Fibrosis in Type 2 Diabetes

EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease

EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease in severely obese people: do they lead to over-referral?

Screening for non -alcoholic fatty liver disease in type 2 diabetes using non-invasive scores and association with diabetic complications

Plasma metabolomic profile in nonalcoholic fatty liver disease

Bile Acid Alterations Are Associated With Insulin Resistance, but Not With NASH, in Obese Subjects

Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance

Use of a metabolomic approach to non-invasively diagnose non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus

Specific Hepatic Sphingolipids Relate to Insulin Resistance, Oxidative Stress, and Inflammation in Nonalcoholic Steatohepatitis

Circulating microRNAs in patients with chronic hepatitis C and non-alcoholic fatty liver disease

Plasma miR-17, miR-20a, miR-20b and miR-122 as potential biomarkers for diagnosis of NAFLD in type 2 diabetes mellitus patients

Gut Microbiome -Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease

Intercept's hotly anticipated NASH drug has to wait for its FDA hearing, thanks to COVID-19

Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes

Remission of Human Type 2 Diabetes Requires Decrease in Liver and Pancreas Fat Content but Is Dependent upon Capacity for β Cell Recovery

Ad Libitum Mediterranean and Low-Fat Diets Both Significantly Reduce Hepatic Steatosis: A Randomized Controlled Trial

Isocaloric Diets High in Animal or Plant Protein Reduce Liver Fat and Inflammation in Individuals With Type 2 Diabetes

Treatment of NAFLD with diet, physical activity and exercise

Fatty Liver Italian Network. Behavior therapy for nonalcoholic fatty liver disease: The need for a multidisciplinary approach

Association of Pharmacological Treatments for Obesity With Weight Loss and Adverse Events: A Systematic Review and Meta-analysis

Efficacy of orlistat in non-alcoholic fatty liver disease: A systematic review and meta-analysis

Effect of Weight Loss Medications on Hepatic Steatosis and Steatohepatitis: A Systematic Review

Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study

Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in Morbidly Obese Patients

Bariatric surgery: a systematic review and meta-analysis

Bariatric surgery in patients with non-alcoholic fatty liver disease -from pathophysiology to clinical effects

DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery

Dynamic changes of muscle insulin sensitivity after metabolic surgery

The mechanisms of action of metformin

Metformin Use and Clinical Outcomes Among Patients With Diabetes Mellitus With or Without Heart Failure or Kidney Dysfunction: Observations From the SAVOR-TIMI 53 Trial

10-year follow-up of intensive glucose control in type 2 diabetes

Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial

A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease

Metformin in non-alcoholic fatty liver disease: A systematic review and meta-analysis

Type 2 diabetes mellitus and risk of hepatocellular carcinoma: spotlight on nonalcoholic fatty liver disease

Pleiotropic mechanisms for the glucose-lowering action of DPP-4 inhibitors

Cardiovascular outcome trials of glucose-lowering medications: an update

Sitagliptin vs. placebo for non-alcoholic fatty liver disease: A randomized controlled trial

Sitagliptin in patients with non-alcoholic steatohepatitis: A randomized, placebo-controlled trial

Effect of Vildagliptin on Hepatic Steatosis

Comparison of the Effects of Glucagon-Like Peptide Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors for Prevention of Major Adverse Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus

Sitagliptin, and Insulin Glargine Added to Metformin: The Effect on Body Weight and Intrahepatic Lipid in Patients With Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease

Effect of Liraglutide Therapy on Liver Fat Content in Patients With Inadequately Controlled Type 2 Diabetes: The Lira-NAFLD Study

Placebo-controlled randomised trial with liraglutide on magnetic resonance endpoints in individuals with type 2 diabetes: a pre-specified secondary study on ectopic fat accumulation

The anti-diabetic drug exenatide, a glucagon-like peptide-1 receptor agonist, counteracts hepatocarcinogenesis through cAMP-PKA-EGFR-STAT3 axis

LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept

Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans

Effects of Novel Dual GIP and GLP-1 Receptor Agonist Tirzepatide on Biomarkers of Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes

SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials

Empagliflozin Effectively Lowers Liver Fat Content in Well-Controlled Type 2 Diabetes: A Randomized, Double-Blind, Phase 4, Placebo-Controlled Trial

The SGLT2 Inhibitor Dapagliflozin Reduces Liver Fat but Does Not Affect Tissue Insulin Sensitivity: A Randomized, Double-Blind, Placebo-Controlled Study With 8-Week Treatment in Type 2 Diabetes Patients

Effect of canagliflozin treatment on hepatic triglyceride content and glucose metabolism in patients with type 2 diabetes

Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study

Effect of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial)

Empagliflozin for the Treatment of Nonalcoholic Steatohepatitis in Patients with Type 2 Diabetes Mellitus

The SGLT2 Inhibitor Canagliflozin Prevents Carcinogenesis in a Mouse Model of Diabetes and Non-Alcoholic Steatohepatitis-Related Hepatocarcinogenesis: Association with SGLT2 Expression in Hepatocellular Carcinoma

Empagliflozin Ameliorates Obesity-Related Cardiac Dysfunction by Regulating Sestrin2-Mediated AMPK-mTOR Signaling and Redox Homeostasis in High-Fat Induced Obese Mice

SGLT1 inhibition: Pros and cons

LIK066 (licogliflozin), an SGLT1/2 inhibitor, robustly decreases ALT and improves markers of hepatic and metabolic health in patients with nonalcoholic fatty liver disease: Interim analysis of a 12-week, randomized, placebo-controlled, Phase 2a study n

PPARγ signaling and metabolism: the good, the bad and the future

Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial

Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis

Randomized, placebocontrolled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis

Pioglitazone for the Primary and Secondary Prevention of Cardiovascular and Renal Outcomes in Patients with or at High Risk of Type 2 Diabetes Mellitus: A Meta-Analysis

Targeting Metabolism, Insulin Resistance, and Diabetes to Treat Nonalcoholic Steatohepatitis

Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled phase IIb study

The Opportunities and Challenges of Peroxisome Proliferator-Activated Receptors Ligands in Clinical Drug Discovery and Development

Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening

Announces-Results-from-Interim-Analysis-of-RESOLVE-IT-Phase-3-Trial-of-Elafibranor-in-Adultswith-NASH-and-Fibrosis.html

Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models

Synthesis , and Evaluation of a Novel Series of Indole Sulfonamide Peroxisome Proliferator Activated Receptor (PPAR) α/γ/δ Triple Activators: Discovery of Lanifibranor, a New Antifibrotic Clinical Candidate

Targeting FXR in Cholestasis

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial

Impact of obeticholic acid on the lipoprotein profile in patients with non-alcoholic steatohepatitis

Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH)

Randomised clinical trial: the efficacy and safety of oltipraz, a liver X receptor alpha-inhibitory dithiolethione in patients with nonalcoholic fatty liver disease

Cenicriviroc for the treatment of non-alcoholic steatohepatitis and liver fibrosis

A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis

Cenicriviroc Treatment for Adults with Nonalcoholic Steatohepatitis and Fibrosis: Final Analysis of the Phase 2b CENTAUR Study

Statin Use and Risk of Cirrhosis and Related Complications in Patients With Chronic Liver Diseases: A Systematic Review and Meta-analysis

Prescription of statins in suspected non-alcoholic fatty liver dise ase and high cardiovascular risk, a population-based study

Ezetimibe decreased nonalcoholic fatty liver disease activity score but not hepatic steatosis

Effect of fenofibrate and niacin on intrahepatic triglyceride content, ve ry low-density lipoprotein kinetics, and insulin action in obese subjects with nonalcoholic fatty liver disease

Effects of free omega-3 carboxylic acids and fenofibrate on liver fat content in patients with hypertriglyceridemia and non-alcoholic fatty liver disease: A double-blind, randomized, placebo-controlled study

Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation

Acetyl -CoA Carboxylase Inhibitor GS-0976 for 12 Weeks Reduces Hepatic De Novo Lipogenesis and Steatosis in Patients With Nonalcoholic Steatohepatitis

Hepatic stearoyl-CoA desaturase-1 deficiency protects mice from carbohydrate-induced adiposity and hepatic steatosis

One-year results of the Global Phase 2b randomized placebo-controlled ARREST Trial of Aramchol, a Stearoyl CoA Desaturasemodulator in NASH patients n

Mitochondrial uncoupling and lifespan

Emerging Pharmacological Targets for the Treatment of Nonalcoholic Fatty Liver Disease, Insulin Resistance, and Type 2 Diabetes

Reversal of Hypertriglyceridemia, Fatty Liver Disease and Insulin Resistance by a Liver-Targeted Mitochondrial Uncoupler

Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats

Controlledrelease mitochondrial protonophore (CRMP) reverses dyslipidemia and hepatic steatosis in dysmetabolic nonhuman primates

Nonalcoholic Fatty Liver Disease and Hypercholesterolemia: Roles of Thyroid Hormones, Metabolites, and Agonists

MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

Nonalcoholic Fatty Liver Disease and Diabetes: Part II: Treatment

Vitamin E Improves Transplant-Free Survival and Hepatic Decompensation Among Patients With Nonalcoholic Steatohepatitis and Advanced Fibrosis

Total fecal microbiota transplantation alleviates high-fat diet-induced steatohepatitis in mice via beneficial regulation of gut microbiota

Efficacy of rifaximin on circulating endotoxins and cytokines in patients with nonalcoholic fatty liver disease