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• W2895834165 abstract "A hepatic comorbidity of metabolic syndrome, known as nonalcoholic fatty liver disease (NAFLD), is increasing in prevalence in conjunction with the pandemics of obesity and diabetes. The spectrum of NAFLD ranges from simple hepatic fat accumulation to a more severe disease termed nonalcoholic steatohepatitis (NASH), involving inflammation, hepatocyte death, and fibrosis. Importantly, NASH is linked to a much higher risk of cirrhosis, liver failure, and hepatocellular carcinoma, as well as an increased risk for nonhepatic malignancies and cardiovascular disease. Interest in the understanding of the disease processes and search for treatments for the spectrum of NAFLD-NASH has increased exponentially, but there are no approved pharmacologic therapies. In this review, we discuss the existing literature supporting insulin-sensitizing thiazolidinedione compounds as potential drug candidates for the treatment of NASH. In addition, we put these results into new context by summarizing recent studies suggesting these compounds alter mitochondrial metabolism by binding and inhibiting the mitochondrial pyruvate carrier. A hepatic comorbidity of metabolic syndrome, known as nonalcoholic fatty liver disease (NAFLD), is increasing in prevalence in conjunction with the pandemics of obesity and diabetes. The spectrum of NAFLD ranges from simple hepatic fat accumulation to a more severe disease termed nonalcoholic steatohepatitis (NASH), involving inflammation, hepatocyte death, and fibrosis. Importantly, NASH is linked to a much higher risk of cirrhosis, liver failure, and hepatocellular carcinoma, as well as an increased risk for nonhepatic malignancies and cardiovascular disease. Interest in the understanding of the disease processes and search for treatments for the spectrum of NAFLD-NASH has increased exponentially, but there are no approved pharmacologic therapies. In this review, we discuss the existing literature supporting insulin-sensitizing thiazolidinedione compounds as potential drug candidates for the treatment of NASH. In addition, we put these results into new context by summarizing recent studies suggesting these compounds alter mitochondrial metabolism by binding and inhibiting the mitochondrial pyruvate carrier. SummaryThis article reviews the recent studies suggesting a potential role for inhibiting mitochondrial pyruvate metabolism as a strategy for treatment of nonalcoholic steatohepatitis. This article reviews the recent studies suggesting a potential role for inhibiting mitochondrial pyruvate metabolism as a strategy for treatment of nonalcoholic steatohepatitis. Interest in better understanding nonalcoholic fatty liver disease (NAFLD) has increased exponentially as a result of the increasing prevalence of the disease and it now is appreciated how significantly the disease impacts overall health. NAFLD is a spectrum of disease that ranges from simple hepatic steatosis to the more severe nonalcoholic steatohepatitis (NASH), involving hepatocellular injury, inflammation, and hepatic fibrosis. Although most individuals with steatosis do not progress to NASH, because of its prevalence, the number of patients that will develop severe forms of the disease is staggering. In the United States, it is estimated that more than 83.1 million people have NAFLD and as many as 27% of these individuals may have NASH.1Estes C. Razavi H. Loomba R. Younossi Z. Sanyal A.J. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease.Hepatology. 2018; 67: 123-133Crossref PubMed Scopus (986) Google Scholar Importantly, NASH increases the risk of developing cirrhosis, liver failure, and hepatocellular carcinoma, as well as an increased predisposition to non–liver-associated diseases such as cardiovascular disease and cancer.2Harlow K.E. Africa J.A. Wells A. Belt P.H. Behling C.A. Jain A.K. Molleston J.P. Newton K.P. Rosenthal P. Vos M.B. Xanthakos S.A. Lavine J.E. Schwimmer J.B. Nonalcoholic Steatohepatitis Clinical Research NetworkClinically actionable hypercholesterolemia and hypertriglyceridemia in children with nonalcoholic fatty liver disease.J Pediatr. 2018; 198: 76-83 e2Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, 3Simon T.G. Bamira D.G. Chung R.T. Weiner R.B. Corey K.E. Nonalcoholic steatohepatitis is associated with cardiac remodeling and dysfunction.Obesity (Silver Spring). 2017; 25: 1313-1316Crossref PubMed Scopus (40) Google Scholar, 4Adams L.A. Anstee Q.M. Tilg H. Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases.Gut. 2017; 66: 1138-1153Crossref PubMed Scopus (599) Google Scholar, 5VanWagner L.B. Wilcox J.E. Colangelo L.A. Lloyd-Jones D.M. Carr J.J. Lima J.A. Lewis C.E. Rinella M.E. Shah S.J. Association of nonalcoholic fatty liver disease with subclinical myocardial remodeling and dysfunction: a population-based study.Hepatology. 2015; 62: 773-783Crossref PubMed Scopus (169) Google Scholar, 6Wongjarupong N. Assavapongpaiboon B. Susantitaphong P. Cheungpasitporn W. Treeprasertsuk S. Rerknimitr R. Chaiteerakij R. Non-alcoholic fatty liver disease as a risk factor for cholangiocarcinoma: a systematic review and meta-analysis.BMC Gastroenterol. 2017; 17: 149Crossref PubMed Scopus (62) Google Scholar Despite this high prevalence and the negative health impact of NASH, there are no approved therapeutic agents for treating this spectrum of conditions. Nutrient oversupply is likely a driving force in developing NAFLD. High levels of dietary fat or sugar, free fatty acids from adipose tissue, and de novo lipogenesis all likely contribute to the overabundance of lipids.7Kawano Y. Cohen D.E. Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease.J Gastroenterol. 2013; 48: 434-441Crossref PubMed Scopus (576) Google Scholar At some point, and because of factors that are still emerging, lipid accumulation activates inflammatory cascades and tissue injury responses that lead to the development of NASH. Multiple cell types in the liver play a role in this progression. The parenchymal cells of the liver, hepatocytes, are the main site of neutral lipid storage and secrete a number of factors that can communicate with other cell types to drive the progression to NASH. Cells of the immune system also play a role through release of inflammatory cytokines and other factors. Finally, hepatic stellate cells (HSCs) are fibroblastic cells that migrate to the site of injury and secrete extracellular matrix components that make up the fibrotic lesions observed histologically in NASH.8Mederacke I. Hsu C.C. Troeger J.S. Huebener P. Mu X. Dapito D.H. Pradere J.P. Schwabe R.F. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology.Nat Commun. 2013; 4: 2823Crossref PubMed Scopus (827) Google Scholar To be considered successful, phase 3 clinical trials for NASH will need to show significant histologic improvements in fibrosis or NAFLD activity scoring (NAS) (assessment of steatosis, hepatocyte death [ballooning], and inflammation) without worsening other histologic end points. Obesity-related insulin resistance and type 2 diabetes are tightly linked to the development of NAFLD and progression to NASH.9Lim H.W. Bernstein D.E. Risk factors for the development of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, including genetics.Clin Liver Dis. 2018; 22: 39-57Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 10Smits M.M. Ioannou G.N. Boyko E.J. Utzschneider K.M. Non-alcoholic fatty liver disease as an independent manifestation of the metabolic syndrome: results of a US national survey in three ethnic groups.J Gastroenterol Hepatol. 2013; 28: 664-670Crossref PubMed Scopus (112) Google Scholar, 11Marchesini G. Bugianesi E. Forlani G. Cerrelli F. Lenzi M. Manini R. Natale S. Vanni E. Villanova N. Melchionda N. Rizzetto M. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome.Hepatology. 2003; 37: 917-923Crossref PubMed Scopus (2211) Google Scholar, 12Choudhury J. Sanyal A.J. Insulin resistance and the pathogenesis of nonalcoholic fatty liver disease.Clin Liver Dis. 2004; 8 (ix): 575-594Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, 13Ballestri S. Zona S. Targher G. Romagnoli D. Baldelli E. Nascimbeni F. Roverato A. Guaraldi G. Lonardo A. Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis.J Gastroenterol Hepatol. 2016; 31: 936-944Crossref PubMed Scopus (421) Google Scholar Accumulation of fat has been linked to impaired insulin signaling via accumulation of specific species of lipids that activate signaling cascades14Jelenik T. Kaul K. Sequaris G. Flogel U. Phielix E. Kotzka J. Knebel B. Fahlbusch P. Horbelt T. Lehr S. Reinbeck A.L. Muller-Wieland D. Esposito I. Shulman G.I. Szendroedi J. Roden M. Mechanisms of insulin resistance in primary and secondary nonalcoholic fatty liver.Diabetes. 2017; 66: 2241-2253Crossref PubMed Scopus (98) Google Scholar, 15Chaurasia B. Summers S.A. Ceramides - lipotoxic inducers of metabolic disorders.Trends Endocrinol Metab. 2015; 26: 538-550Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar (Figure 1). The cause and effect relationship between hepatic steatosis and insulin resistance is not always clear,16Farese Jr., R.V. Zechner R. Newgard C.B. Walther T.C. The problem of establishing relationships between hepatic steatosis and hepatic insulin resistance.Cell Metab. 2012; 15: 570-573Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar but abundant evidence suggests that insulin resistance may drive local and systemic alterations in metabolism that promote liver lipid accumulation (Figure 1). For instance, hyperinsulinemia in insulin-resistant states stimulates hepatic de novo lipogenesis,17Ferre P. Foufelle F. Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c.Diabetes Obes Metab. 2010; 12: 83-92Crossref PubMed Scopus (486) Google Scholar and this newly synthesized lipid comprises roughly 25% of the hepatic triglyceride accumulating in NAFLD.18Donnelly K.L. Smith C.I. Schwarzenberg S.J. Jessurun J. Boldt M.D. Parks E.J. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.J Clin Invest. 2005; 115: 1343-1351Crossref PubMed Scopus (2412) Google Scholar Insulin-resistant adipose tissue is linked to higher rates of basal lipolysis and thus exposure of the liver to increased plasma free fatty acid concentrations.19Holt H.B. Wild S.H. Wood P.J. Zhang J. Darekar A.A. Dewbury K. Poole R.B. Holt R.I. Phillips D.I. Byrne C.D. Non-esterified fatty acid concentrations are independently associated with hepatic steatosis in obese subjects.Diabetologia. 2006; 49: 141-148Crossref PubMed Scopus (75) Google Scholar, 20Fabbrini E. Mohammed B.S. Magkos F. Korenblat K.M. Patterson B.W. Klein S. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease.Gastroenterology. 2008; 134: 424-431Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar Indeed, roughly 60% of hepatic triglycerides in human NAFLD subjects are derived from plasma fatty acids.18Donnelly K.L. Smith C.I. Schwarzenberg S.J. Jessurun J. Boldt M.D. Parks E.J. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.J Clin Invest. 2005; 115: 1343-1351Crossref PubMed Scopus (2412) Google Scholar For some time now, it has been hypothesized that interventions to treat insulin resistance will have utility for concomitant attenuation of NAFLD and NASH. Given the tight linkage to insulin resistance, the insulin-sensitizing thiazolidinediones (TZDs) rosiglitazone and pioglitazone have been evaluated extensively as NAFLD treatments.21Neuschwander-Tetri B.A. Brunt E.M. Wehmeier K.R. Oliver D. Bacon B.R. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone.Hepatology. 2003; 38: 1008-1017Crossref PubMed Scopus (718) Google Scholar, 22Sanyal A.J. Chalasani N. Kowdley K.V. McCullough A. Diehl A.M. Bass N.M. Neuschwander-Tetri B.A. Lavine J.E. Tonascia J. Unalp A. Van Natta M. Clark J. Brunt E.M. Kleiner D.E. Hoofnagle J.H. Robuck P.R. Nash C.R.N. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.N Engl J Med. 2010; 362: 1675-1685Crossref PubMed Scopus (2256) Google Scholar, 23Caldwell S.H. Hespenheide E.E. Redick J.A. Iezzoni J.C. Battle E.H. Sheppard B.L. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis.Am J Gastroenterol. 2001; 96: 519-525Crossref PubMed Google Scholar, 24Neuschwander-Tetri B.A. Brunt E.M. Wehmeier K.R. Sponseller C.A. Hampton K. Bacon B.R. Interim results of a pilot study demonstrating the early effects of the PPAR-gamma ligand rosiglitazone on insulin sensitivity, aminotransferases, hepatic steatosis and body weight in patients with non-alcoholic steatohepatitis.J Hepatol. 2003; 38: 434-440Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 25Promrat K. Lutchman G. Uwaifo G.I. Freedman R.J. Soza A. Heller T. Doo E. Ghany M. Premkumar A. Park Y. Liang T.J. Yanovski J.A. Kleiner D.E. Hoofnagle J.H. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis.Hepatology. 2004; 39: 188-196Crossref PubMed Scopus (669) Google Scholar, 26Ratziu V. Giral P. Jacqueminet S. Charlotte F. Hartemann-Heurtier A. Serfaty L. Podevin P. Lacorte J.M. Bernhardt C. Bruckert E. Grimaldi A. Poynard T. Group L.S. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial.Gastroenterology. 2008; 135: 100-110Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar, 27Aithal G.P. Thomas J.A. Kaye P.V. Lawson A. Ryder S.D. Spendlove I. Austin A.S. Freeman J.G. Morgan L. Webber J. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis.Gastroenterology. 2008; 135: 1176-1184Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar, 28Ratziu V. Charlotte F. Bernhardt C. Giral P. Halbron M. Lenaour G. Hartmann-Heurtier A. Bruckert E. Poynard T. Group L.S. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial.Hepatology. 2010; 51: 445-453Crossref PubMed Scopus (286) Google Scholar These antidiabetic and anti-inflammatory compounds are agonists of the nuclear transcription factor peroxisome proliferator-activated receptor γ (PPARγ),29Lehmann J.M. Moore L.B. Smith-Oliver T.A. Wilkison W.O. Willson T.M. Kliewer S.A. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma).J Biol Chem. 1995; 270: 12953-12956Crossref PubMed Scopus (3459) Google Scholar which activates a transcriptional program driving fatty acid storage and adipocyte differentiation. Unfortunately, PPARγ activation is associated with a number of side effects such as weight gain, edema, and bone mineral density loss.30Soccio R.E. Chen E.R. Lazar M.A. Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes.Cell Metab. 2014; 20: 573-591Abstract Full Text Full Text PDF PubMed Scopus (329) Google Scholar Rosiglitazone, the most potent PPARγ agonist, was linked to increased cardiovascular mortality,31Dormandy J.A. Charbonnel B. Eckland D.J. Erdmann E. Massi-Benedetti M. Moules I.K. Skene A.M. Tan M.H. Lefebvre P.J. Murray G.D. Standl E. Wilcox R.G. Wilhelmsen L. Betteridge J. Birkeland K. Golay A. Heine R.J. Koranyi L. Laakso M. Mokan M. Norkus A. Pirags V. Podar T. Scheen A. Scherbaum W. Schernthaner G. Schmitz O. Skrha J. Smith U. Taton J. Investigators PROactive Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.Lancet. 2005; 366: 1279-1289Abstract Full Text Full Text PDF PubMed Scopus (3692) Google Scholar, 32Kernan W.N. Viscoli C.M. Furie K.L. Young L.H. Inzucchi S.E. Gorman M. Guarino P.D. Lovejoy A.M. Peduzzi P.N. Conwit R. Brass L.M. Schwartz G.G. Adams Jr., H.P. Berger L. Carolei A. Clark W. Coull B. Ford G.A. Kleindorfer D. O'Leary J.R. Parsons M.W. Ringleb P. Sen S. Spence J.D. Tanne D. Wang D. Winder T.R. IRIS Trial Investigators. Pioglitazone after ischemic stroke or transient ischemic attack.N Engl J Med. 2016; 374: 1321-1331Crossref PubMed Scopus (701) Google Scholar, 33FDA Drug Safety Communication. FDA eliminates the Risk Evaluation and Mitigation Strategy (REMS) for rosiglitazone-containing diabetes medicines. December 16, Available from: https://www.fda.gov/Drugs/DrugSafety/ucm476466.htm. Accessed: July 18, 2018.Google Scholar which later was discounted, but caused clinical use of TZDs to plummet.34Sharma M. Nazareth I. Petersen I. Trends in incidence, prevalence and prescribing in type 2 diabetes mellitus between 2000 and 2013 in primary care: a retrospective cohort study.BMJ Open. 2016; 6: e010210Crossref PubMed Scopus (195) Google Scholar In addition to their strong insulin-sensitizing effects in high-fat diet–fed rodents, TZDs markedly reduced inflammation35Nan Y.M. Han F. Kong L.B. Zhao S.X. Wang R.Q. Wu W.J. Yu J. Adenovirus-mediated peroxisome proliferator activated receptor gamma overexpression prevents nutritional fibrotic steatohepatitis in mice.Scand J Gastroenterol. 2011; 46: 358-369Crossref PubMed Scopus (51) Google Scholar, 36Yu J. Zhang S. Chu E.S. Go M.Y. Lau R.H. Zhao J. Wu C.W. Tong L. Zhao J. Poon T.C. Sung J.J. Peroxisome proliferator-activated receptors gamma reverses hepatic nutritional fibrosis in mice and suppresses activation of hepatic stellate cells in vitro.Int J Biochem Cell Biol. 2010; 42: 948-957Crossref PubMed Scopus (63) Google Scholar and prevented37Kawaguchi K. Sakaida I. Tsuchiya M. Omori K. Takami T. Okita K. Pioglitazone prevents hepatic steatosis, fibrosis, and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet.Biochem Biophys Res Commun. 2004; 315: 187-195Crossref PubMed Scopus (137) Google Scholar or reversed38Uto H. Nakanishi C. Ido A. Hasuike S. Kusumoto K. Abe H. Numata M. Nagata K. Hayashi K. Tsubouchi H. The peroxisome proliferator-activated receptor-gamma agonist, pioglitazone, inhibits fat accumulation and fibrosis in the livers of rats fed a choline-deficient, l-amino acid-defined diet.Hepatol Res. 2005; 32: 235-242PubMed Google Scholar hepatic fibrosis, including direct effects on stellate cell activation. Unfortunately, although early studies conducted in human beings produced results that generally were positive for improving steatosis and plasma markers for liver injury such as alanine aminotransferase, they largely did not result in significant histologic improvement with TZD therapy.21Neuschwander-Tetri B.A. Brunt E.M. Wehmeier K.R. Oliver D. Bacon B.R. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone.Hepatology. 2003; 38: 1008-1017Crossref PubMed Scopus (718) Google Scholar, 22Sanyal A.J. Chalasani N. Kowdley K.V. McCullough A. Diehl A.M. Bass N.M. Neuschwander-Tetri B.A. Lavine J.E. Tonascia J. Unalp A. Van Natta M. Clark J. Brunt E.M. Kleiner D.E. Hoofnagle J.H. Robuck P.R. Nash C.R.N. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.N Engl J Med. 2010; 362: 1675-1685Crossref PubMed Scopus (2256) Google Scholar, 23Caldwell S.H. Hespenheide E.E. Redick J.A. Iezzoni J.C. Battle E.H. Sheppard B.L. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis.Am J Gastroenterol. 2001; 96: 519-525Crossref PubMed Google Scholar, 24Neuschwander-Tetri B.A. Brunt E.M. Wehmeier K.R. Sponseller C.A. Hampton K. Bacon B.R. Interim results of a pilot study demonstrating the early effects of the PPAR-gamma ligand rosiglitazone on insulin sensitivity, aminotransferases, hepatic steatosis and body weight in patients with non-alcoholic steatohepatitis.J Hepatol. 2003; 38: 434-440Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 25Promrat K. Lutchman G. Uwaifo G.I. Freedman R.J. Soza A. Heller T. Doo E. Ghany M. Premkumar A. Park Y. Liang T.J. Yanovski J.A. Kleiner D.E. Hoofnagle J.H. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis.Hepatology. 2004; 39: 188-196Crossref PubMed Scopus (669) Google Scholar, 26Ratziu V. Giral P. Jacqueminet S. Charlotte F. Hartemann-Heurtier A. Serfaty L. Podevin P. Lacorte J.M. Bernhardt C. Bruckert E. Grimaldi A. Poynard T. Group L.S. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial.Gastroenterology. 2008; 135: 100-110Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar, 27Aithal G.P. Thomas J.A. Kaye P.V. Lawson A. Ryder S.D. Spendlove I. Austin A.S. Freeman J.G. Morgan L. Webber J. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis.Gastroenterology. 2008; 135: 1176-1184Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar, 28Ratziu V. Charlotte F. Bernhardt C. Giral P. Halbron M. Lenaour G. Hartmann-Heurtier A. Bruckert E. Poynard T. Group L.S. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial.Hepatology. 2010; 51: 445-453Crossref PubMed Scopus (286) Google Scholar, 39He L. Liu X. Wang L. Yang Z. Thiazolidinediones for nonalcoholic steatohepatitis: a meta-analysis of randomized clinical trials.Medicine (Baltimore). 2016; 95: e4947Crossref PubMed Scopus (33) Google Scholar In the majority of the early clinical NASH trials with TZD compounds, drug exposures were quite low and for a limited duration, likely in attempt to avoid these clinical side effects. Interestingly, a more recent trial using 45 mg/day pioglitazone for 18–36 months resulted in NASH histologic improvement, including fibrosis score improvement, compared with placebo, without significant safety issues.40Cusi K. Orsak B. Bril F. Lomonaco R. Hecht J. Ortiz-Lopez C. Tio F. Hardies J. Darland C. Musi N. Webb A. Portillo-Sanchez P. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized, controlled trial.Ann Intern Med. 2016; 165: 305-315Crossref PubMed Scopus (553) Google Scholar Although the response to pioglitazone was quite variable in these subjects, it was shown that the degree of histologic improvements was correlated with blood pioglitazone (as well as active drug metabolite hydroxypioglitazone and ketopioglitazone) concentrations.41Kawaguchi-Suzuki M. Bril F. Kalavalapalli S. Cusi K. Frye R.F. Concentration-dependent response to pioglitazone in nonalcoholic steatohepatitis.Aliment Pharmacol Ther. 2017; 46: 56-61Crossref PubMed Scopus (13) Google Scholar The likelihood of improvement also was linked to genetic variation in the CYP2C8 gene,42Kawaguchi-Suzuki M. Cusi K. Bril F. Gong Y. Langaee T. Frye R.F. A genetic score associates with pioglitazone response in patients with non-alcoholic steatohepatitis.Front Pharmacol. 2018; 9: 752Crossref PubMed Scopus (15) Google Scholar which encodes the cytochrome P450 enzyme isoform that metabolizes pioglitazone.43Jaakkola T. Laitila J. Neuvonen P.J. Backman J.T. Pioglitazone is metabolised by CYP2C8 and CYP3A4 in vitro: potential for interactions with CYP2C8 inhibitors.Basic Clin Pharmacol Toxicol. 2006; 99: 44-51Crossref PubMed Scopus (125) Google Scholar In addition, a recent meta-analysis of 8 randomized clinical trials evaluating pioglitazone or rosiglitazone in NASH concluded that NASH resolution and fibrosis improvement is observed with pioglitazone, but not rosiglitazone.44Musso G. Cassader M. Paschetta E. Gambino R. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: a meta-analysis.JAMA Intern Med. 2017; 177: 633-640Crossref PubMed Scopus (235) Google Scholar, 45Bril F. Kalavalapalli S. Clark V.C. Lomonaco R. Soldevila-Pico C. Liu I.C. Orsak B. Tio F. Cusi K. Response to pioglitazone in patients with nonalcoholic steatohepatitis with vs without type 2 diabetes.Clin Gastroenterol Hepatol. 2018; 16: 558-566 e2Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar Because pioglitazone shows significantly weaker affinity for PPARγ compared with rosiglitazone,29Lehmann J.M. Moore L.B. Smith-Oliver T.A. Wilkison W.O. Willson T.M. Kliewer S.A. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma).J Biol Chem. 1995; 270: 12953-12956Crossref PubMed Scopus (3459) Google Scholar one must consider whether additional molecular targets of TZDs are responsible for the improvements of NASH observed with pioglitazone. Interestingly, a number of PPARγ-sparing TZD compounds, including Metabolic Solutions Development Company (MSDC)-0160 and MSDC-0602, recently were synthesized and shown to have potent insulin-sensitizing and antifibrotic effects.46Chen Z. Vigueira P.A. Chambers K.T. Hall A.M. Mitra M.S. Qi N. McDonald W.G. Colca J.R. Kletzien R.F. Finck B.N. Insulin resistance and metabolic derangements in obese mice are ameliorated by a novel peroxisome proliferator-activated receptor gamma-sparing thiazolidinedione.J Biol Chem. 2012; 287: 23537-23548Crossref PubMed Scopus (93) Google Scholar, 47Colca J.R. VanderLugt J.T. Adams W.J. Shashlo A. McDonald W.G. Liang J. Zhou R. Orloff D.G. Clinical proof-of-concept study with MSDC-0160, a prototype mTOT-modulating insulin sensitizer.Clin Pharmacol Ther. 2013; 93: 352-359Crossref PubMed Scopus (61) Google Scholar, 48McCommis K.S. Hodges W.T. Brunt E.M. Nalbantoglu I. McDonald W.G. Holley C. Fujiwara H. Schaffer J.E. Colca J.R. Finck B.N. Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis.Hepatology. 2017; 65: 1543-1556Crossref PubMed Scopus (85) Google Scholar These compounds show PPARγ-binding affinities that are roughly an order of magnitude less than pioglitazone, and 2 orders of magnitude less than rosiglitazone.46Chen Z. Vigueira P.A. Chambers K.T. Hall A.M. Mitra M.S. Qi N. McDonald W.G. Colca J.R. Kletzien R.F. Finck B.N. Insulin resistance and metabolic derangements in obese mice are ameliorated by a novel peroxisome proliferator-activated receptor gamma-sparing thiazolidinedione.J Biol Chem. 2012; 287: 23537-23548Crossref PubMed Scopus (93) Google Scholar MSDC-0160 and MSDC-0602 also show extremely low PPARγ luciferase reporter activation,46Chen Z. Vigueira P.A. Chambers K.T. Hall A.M. Mitra M.S. Qi N. McDonald W.G. Colca J.R. Kletzien R.F. Finck B.N. Insulin resistance and metabolic derangements in obese mice are ameliorated by a novel peroxisome proliferator-activated receptor gamma-sparing thiazolidinedione.J Biol Chem. 2012; 287: 23537-23548Crossref PubMed Scopus (93) Google Scholar, 49Bolten C.W. Blanner P.M. McDonald W.G. Staten N.R. Mazzarella R.A. Arhancet G.B. Meier M.F. Weiss D.J. Sullivan P.M. Hromockyj A.E. Kletzien R.F. Colca J.R. Insulin sensitizing pharmacology of thiazolidinediones correlates with mitochondrial gene expression rather than activation of PPAR gamma.Gene Regul Syst Bio. 2007; 1: 73-82PubMed Google Scholar and treatment with MSDC compounds does not induce PPARγ-target genes in cultured adipocytes46Chen Z. Vigueira P.A. Chambers K.T. Hall A.M. Mitra M.S. Qi N. McDonald W.G. Colca J.R. Kletzien R.F. Finck B.N. Insulin resistance and metabolic derangements in obese mice are ameliorated by a novel peroxisome proliferator-activated receptor gamma-sparing thiazolidinedione.J Biol Chem. 2012; 287: 23537-23548Crossref PubMed Scopus (93) Google Scholar or cause weight gain in a clinical trial.47Colca J.R. VanderLugt J.T. Adams W.J. Shashlo A. McDonald W.G. Liang J. Zhou R. Orloff D.G. Clinical proof-of-concept study with MSDC-0160, a prototype mTOT-modulating insulin sensitizer.Clin Pharmacol Ther. 2013; 93: 352-359Crossref PubMed Scopus (61) Google Scholar However, the studies conducted in mice show strong anti-inflammatory effects and evidence of adipose tissue browning.46Chen Z. Vigueira P.A. Chambers K.T. Hall A.M. Mitra M.S. Qi N. McDonald W.G. Colca J.R. Kletzien R.F. Finck B.N. Insulin resistance and metabolic derangements in obese mice are ameliorated by a novel peroxisome proliferator-activated receptor gamma-sparing thiazolidinedione.J Biol Chem. 2012; 287: 23537-23548Crossref PubMed Scopus (93) Google Scholar These PPARγ-sparing TZD compounds also improve insulin sensitivity in both mouse models46Chen Z. Vigueira P.A. Chambers K.T. Hall A.M. Mitra M.S. Qi N. McDonald W.G. Colca J.R. Kletzien R.F. Finck B.N. Insulin resistance and metabolic derangements in obese mice are ameliorated by a novel peroxisome proliferator-activated receptor gamma-sparing thiazolidinedione.J Biol Chem. 2012; 287: 23537-23548Crossref PubMed Scopus (93) Google Scholar and in clinical trials.47Colca J.R. VanderLugt J.T. Adams W.J. Shashlo A. McDonald W.G. Liang J. Zhou R. Orloff D.G. Clinical proof-of-concept study with MSDC-0160, a prototype mTOT-modulating insulin sensitizer.Clin Pharmacol Ther. 2013; 93: 352-359Crossref PubMed Scopus (61) Google Scholar In addition, the potassium salt of MSDC-0602, MSDC-0602K, reduced liver injury in a mouse model of NASH by" @default.
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• W2895834165 date "2019-01-01" @default.
• W2895834165 modified "2023-10-02" @default.
• W2895834165 title "Treating Hepatic Steatosis and Fibrosis by Modulating Mitochondrial Pyruvate Metabolism" @default.
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• W2895834165 doi "https://doi.org/10.1016/j.jcmgh.2018.09.017" @default.
• W2895834165 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6352854" @default.

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