Metabolic Targets in Nonalcoholic Fatty Liver Disease
2019; Elsevier BV; Volume: 8; Issue: 2 Linguagem: Inglês
10.1016/j.jcmgh.2019.04.007
ISSN2352-345X
AutoresWilliam P. Esler, Kendra K. Bence,
Tópico(s)Alcohol Consumption and Health Effects
ResumoThe prevalence and diagnosis of nonalcoholic fatty liver disease (NAFLD) is on the rise worldwide and currently has no FDA-approved pharmacotherapy. The increase in disease burden of NAFLD and a more severe form of this progressive liver disease, nonalcoholic steatohepatitis (NASH), largely mirrors the increase in obesity and type 2 diabetes (T2D) and reflects the hepatic manifestation of an altered metabolic state. Indeed, metabolic syndrome, defined as a constellation of obesity, insulin resistance, hyperglycemia, dyslipidemia and hypertension, is the major risk factor predisposing the NAFLD and NASH. There are multiple potential pharmacologic strategies to rebalance aspects of disordered metabolism in NAFLD. These include therapies aimed at reducing hepatic steatosis by directly modulating lipid metabolism within the liver, inhibiting fructose metabolism, altering delivery of free fatty acids from the adipose to the liver by targeting insulin resistance and/or adipose metabolism, modulating glycemia, and altering pleiotropic metabolic pathways simultaneously. Emerging data from human genetics also supports a role for metabolic drivers in NAFLD and risk for progression to NASH. In this review, we highlight the prominent metabolic drivers of NAFLD pathogenesis and discuss the major metabolic targets of NASH pharmacotherapy. The prevalence and diagnosis of nonalcoholic fatty liver disease (NAFLD) is on the rise worldwide and currently has no FDA-approved pharmacotherapy. The increase in disease burden of NAFLD and a more severe form of this progressive liver disease, nonalcoholic steatohepatitis (NASH), largely mirrors the increase in obesity and type 2 diabetes (T2D) and reflects the hepatic manifestation of an altered metabolic state. Indeed, metabolic syndrome, defined as a constellation of obesity, insulin resistance, hyperglycemia, dyslipidemia and hypertension, is the major risk factor predisposing the NAFLD and NASH. There are multiple potential pharmacologic strategies to rebalance aspects of disordered metabolism in NAFLD. These include therapies aimed at reducing hepatic steatosis by directly modulating lipid metabolism within the liver, inhibiting fructose metabolism, altering delivery of free fatty acids from the adipose to the liver by targeting insulin resistance and/or adipose metabolism, modulating glycemia, and altering pleiotropic metabolic pathways simultaneously. Emerging data from human genetics also supports a role for metabolic drivers in NAFLD and risk for progression to NASH. In this review, we highlight the prominent metabolic drivers of NAFLD pathogenesis and discuss the major metabolic targets of NASH pharmacotherapy. SummaryThis review highlights the major metabolic drivers of nonalcoholic fatty liver disease pathogenesis and gives a current overview of the treatment landscape for nonalcoholic steatohepatitis. This review highlights the major metabolic drivers of nonalcoholic fatty liver disease pathogenesis and gives a current overview of the treatment landscape for nonalcoholic steatohepatitis. Nonalcoholic fatty liver disease (NAFLD) is a constellation of conditions that originates with excess accumulation of fat within the liver (defined as >5%). Nonalcoholic steatohepatitis (NASH) is a clinical and histological subset of NAFLD that is associated with increased all-cause mortality, cirrhosis and end-stage liver disease, increased cardiovascular mortality, and increased incidence of both liver-related and non–liver-related cancers.1Sanyal A.J. Friedman S.L. McCullough A.J. Dimick-Santos L. American Association for the Study of Liver D, United States F, Drug A. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop.Hepatology. 2015; 61: 1392-1405Crossref PubMed Scopus (0) Google Scholar NASH is diagnosed clinically by liver biopsy demonstrating steatosis, inflammation, and cytological ballooning of liver hepatocytes, often with varying degrees of fibrosis. NASH progresses with increasing degrees of fibrosis, with cirrhosis developing in a subset of patients,1Sanyal A.J. Friedman S.L. McCullough A.J. Dimick-Santos L. American Association for the Study of Liver D, United States F, Drug A. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop.Hepatology. 2015; 61: 1392-1405Crossref PubMed Scopus (0) Google Scholar with the most common complication of cirrhosis being hepatocellular carcinoma.2Khan F.Z. Perumpail R.B. Wong R.J. Ahmed A. Advances in hepatocellular carcinoma: Nonalcoholic steatohepatitis-related hepatocellular carcinoma.World J Hepatol. 2015; 7: 2155-2161Crossref PubMed Scopus (30) Google Scholar Metabolic perturbations, including insulin resistance, impaired glycemic control, and altered lipid metabolism, have been hypothesized to contribute to the molecular pathogenesis of NAFLD and NASH (Figure 1). Steatosis is a necessary but not sufficient component of the pathogenesis of NASH.3Day C.P. James O.F. Hepatic steatosis: innocent bystander or guilty party?.Hepatology. 1998; 27: 1463-1466Crossref PubMed Scopus (329) Google Scholar Consistent with this, multiple studies have demonstrated that the severity of steatosis predicts the risk of concomitant steatohepatitis as well as the risk of progression to cirrhosis.4Reeves H.L. Burt A.D. Wood S. Day C.P. 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Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.Nat Genet. 2008; 40: 1461-1465Crossref PubMed Scopus (1500) Google Scholar, 8Rotman Y. Koh C. Zmuda J.M. Kleiner D.E. Liang T.J. Nash C.R.N. The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease.Hepatology. 2010; 52: 894-903Crossref PubMed Scopus (284) Google Scholar These observations taken together provide molecular evidence that steatosis is a key pathogenic factor in NASH. Hepatic steatosis is a consequence of an imbalance in triglyceride (TG) production or uptake into the liver and clearance or removal (Figure 1).9Cohen J.C. Horton J.D. Hobbs H.H. Human fatty liver disease: old questions and new insights.Science. 2011; 332: 1519-1523Crossref PubMed Scopus (1167) Google Scholar Elevated body mass index is a significant risk factor for steatosis10Browning J.D. Szczepaniak L.S. Dobbins R. Nuremberg P. Horton J.D. Cohen J.C. Grundy S.M. Hobbs H.H. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.Hepatology. 2004; 40: 1387-1395Crossref PubMed Scopus (2488) Google Scholar suggesting that excess caloric intake and obesity contribute to the development of NAFLD. Altering the balance of hepatic TG accumulation and removal by either (or both) reducing fat production or promoting fat clearance is likewise expected to reduce steatosis. Amelioration of steatosis in turn is hypothesized to reduce buildup of lipotoxic lipid species, suppress hepatic inflammation, and subsequently reduce fibrogenesis (Figure 1). Indeed, studies in animal models have demonstrated that multiple modalities which reduce steatosis result in downstream improvements in hepatic inflammation and fibrosis.11Honda Y. Imajo K. Kato T. Kessoku T. Ogawa Y. Tomeno W. Kato S. Mawatari H. Fujita K. Yoneda M. Saito S. Nakajima A. The selective SGLT2 inhibitor ipragliflozin has a therapeutic effect on nonalcoholic steatohepatitis in mice.PLoS One. 2016; 11: e0146337Crossref PubMed Scopus (23) Google Scholar, 12Ji G. Wang Y. Deng Y. Li X. Jiang Z. Resveratrol ameliorates hepatic steatosis and inflammation in methionine/choline-deficient diet-induced steatohepatitis through regulating autophagy.Lipids Health Dis. 2015; 14: 134Crossref PubMed Scopus (32) Google Scholar, 13Kita Y. Takamura T. Misu H. Ota T. Kurita S. Takeshita Y. Uno M. Matsuzawa-Nagata N. Kato K. Ando H. Fujimura A. Hayashi K. Kimura T. Ni Y. Otoda T. Miyamoto K. Zen Y. Nakanuma Y. Kaneko S. Metformin prevents and reverses inflammation in a non-diabetic mouse model of nonalcoholic steatohepatitis.PLoS One. 2012; 7: e43056Crossref PubMed Scopus (74) Google Scholar, 14Klein T. Fujii M. Sandel J. Shibazaki Y. Wakamatsu K. Mark M. Yoneyama H. Linagliptin alleviates hepatic steatosis and inflammation in a mouse model of non-alcoholic steatohepatitis.Med Mol Morphol. 2014; 47: 137-149Crossref PubMed Scopus (27) Google Scholar, 15Liu W. Struik D. Nies V.J. Jurdzinski A. Harkema L. de Bruin A. Verkade H.J. Downes M. Evans R.M. van Zutphen T. Jonker J.W. Effective treatment of steatosis and steatohepatitis by fibroblast growth factor 1 in mouse models of nonalcoholic fatty liver disease.Proc Natl Acad Sci U S A. 2016; 113: 2288-2293Crossref PubMed Google Scholar, 16Morrison M.C. Liang W. Mulder P. Verschuren L. Pieterman E. Toet K. Heeringa P. Wielinga P.Y. Kooistra T. Kleemann R. Mirtoselect, an anthocyanin-rich bilberry extract, attenuates non-alcoholic steatohepatitis and associated fibrosis in ApoE( *)3Leiden mice.J Hepatol. 2015; 62: 1180-1186Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 17Qiang X. Xu L. Zhang M. Zhang P. Wang Y. Wang Y. Zhao Z. Chen H. Liu X. Zhang Y. Demethyleneberberine attenuates non-alcoholic fatty liver disease with activation of AMPK and inhibition of oxidative stress.Biochem Biophys Res Commun. 2016; 472: 603-609Crossref PubMed Scopus (22) Google Scholar, 18Soares e Silva A.K. de Oliveira Cipriano Torres D. dos Santos Gomes F.O. dos Santos Silva B. Lima Ribeiro E. Costa Oliveira A. dos Santos L.A. de Lima Mdo C. Pitta Ida R. Peixoto C.A. LPSF/GQ-02 inhibits the development of hepatic steatosis and inflammation in a mouse model of non-alcoholic fatty liver disease (NAFLD).PLoS One. 2015; 10: e0123787Crossref PubMed Scopus (6) Google Scholar, 19Staels B. Rubenstrunk A. Noel B. Rigou G. Delataille P. Millatt L.J. Baron M. Lucas A. Tailleux A. Hum D.W. Ratziu V. Cariou B. Hanf R. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.Hepatology. 2013; 58: 1941-1952Crossref PubMed Scopus (186) Google Scholar, 20Verbeek J. Lannoo M. Pirinen E. Ryu D. Spincemaille P. Vander Elst I. Windmolders P. Thevissen K. Cammue B.P. van Pelt J. Fransis S. Van Eyken P. Ceuterick-De Groote C. Van Veldhoven P.P. Bedossa P. Nevens F. Auwerx J. Cassiman D. Roux-en-y gastric bypass attenuates hepatic mitochondrial dysfunction in mice with non-alcoholic steatohepatitis.Gut. 2015; 64: 673-683Crossref PubMed Scopus (33) Google Scholar, 21Wada T. Miyashita Y. Sasaki M. Aruga Y. Nakamura Y. Ishii Y. Sasahara M. Kanasaki K. Kitada M. Koya D. Shimano H. Tsuneki H. Sasaoka T. Eplerenone ameliorates the phenotypes of metabolic syndrome with NASH in liver-specific SREBP-1c Tg mice fed high-fat and high-fructose diet.Am J Physiol Endocrinol Metab. 2013; 305: E1415-E1425Crossref PubMed Scopus (0) Google Scholar Perhaps the most compelling data in support of targeting metabolic pathways in NASH comes from the bariatric surgery literature. Bariatric surgery leads to restoration of energy balance and improvements in metabolic homeostasis resulting in amelioration of steatosis and marked downstream improvements in, or resolution of, NASH in people. Meta-analysis of multiple bariatric surgery studies demonstrates that this improvement in steatosis observed in 92% of patients is also accompanied by improved steatohepatitis in 81%, lower fibrosis in 66%, and complete resolution in 70% of patients with NASH.22Mummadi R.R. Kasturi K.S. Chennareddygari S. Sood G.K. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis.Clin Gastroenterol Hepatol. 2008; 6: 1396-1402Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar Similarly, weight loss in patients with NASH produced by intense nutritional counseling has also been reported to reduce steatosis leading to improvements in NASH resolution.23Huang M.A. Greenson J.K. Chao C. Anderson L. Peterman D. Jacobson J. Emick D. Lok A.S. Conjeevaram H.S. One-year intense nutritional counseling results in histological improvement in patients with non-alcoholic steatohepatitis: a pilot study.Am J Gastroenterol. 2005; 100: 1072-1081Crossref PubMed Scopus (328) Google Scholar Emerging data also suggest that at least some pharmacological agents that principally target metabolic drivers of steatosis lead to downstream improvements in NASH resolution or fibrosis when administered to patients with NASH with fibrosis, making this an attractive therapeutic angle (vide infra and see Table 1).Table 1Mechanisms of Action and Associated Pharmacotherapies With Clinical Data in NAFLD/NASHMechanism of actionDrug nameCurrent development statusKey clinical data summaryClinicalTrials.Gov identifier for key studiesLipid metabolism pathway modulatorsACC inhibitorPF-05175157 (SM)Ph2—discontinuedSystemically distributed, DNL inhibition, and stimulation of fatty acid oxidation in healthy volunteers. Discontinued due to undisclosed safety concernNCT01792635MK-4074 (SM)Ph1—discontinuedLiver directed exposure, Hepatic DNL inhibition and steatosis lowering in NAFLD subjects; discontinued due to TG elevationsNCT01431521GS-0976 (SM)Ph2Liver directed exposure, DNL inhibition, and steatosis lowering in NAFLD patientsNCT02856555PF-05221304 (SM)Ph2Liver directed exposure, DNL inhibition, no TG increase in healthy subjects at doses which inhibit DNL ≤80%NCT03448172NCT03248882FAS inhibitorTVB-2640 (SM)Ph2DNL inhibition in healthy subjectsNone listedDGAT2 inhibitorIONIS-DGAT2rx (ASO)Ph2Ph1 dose-escalation study completed in healthy overweight subjectsNCT03334214PF-06427878 (SM)Ph1 -discontinuedSteatosis lowering in overweight subjects—discontinued due to human PK profileNCT02855177PF-06865571 (SM)Ph1b/Ph2None disclosedNCT03513588NCT03776175Nuclear hormone receptor agonistsPPARγ agonistPioglitazone (SM)Approved T2D, exploratory studies for NASHImprovements in steatosis, NAS, NASH resolution, and fibrosisNCT00063622NCT00994682PPARα agonistFenofibrate (SM)Approved for dyslipidemia, exploratory studies in NAFLD/NASHNo apparent direct improvements in NASH endpoints or steatosis in small exploratory studiesNCT00262964NCT02354976PPARδ agonistGW501516 (SM)Ph2—discontinuedSteatosis lowering in subjects with NAFLDNAPPARα/δ agonistElafibranor (SM)Ph3Failed to meet protocol specified primary endpoint in Ph2, modest improvement relative to placebo in post hoc definition of NASH resolution, improvement in cardio metabolic parameters notedNCT01694849NCT02704403PPARα/γ agonistSaroglitazar (SM)Approved for dyslipidemia in T2D patients in India, Ph2 for NASHNAFLD/NASH data pendingNCT03061721FXRObeticholic acid (SM)Conditional approval for PBC, Ph3 for NASH and cirrhosis as a result of NASHImprovements in all components of NAS, NASH resolution and fibrosis, mild elevations in LDL, reductions in HDL, increased incidence of pruritusNCT01265498NCT02548351NCT03439254GS-9674 (SM)Ph2Reduction in steatosis and increased incidence of pruritus at 100-mg dose; 30-mg dose (currently being evaluated in ongoing Ph2 monotherapy and combination Ph2 biopsy study) produced very modest relative liver fat reduction (3.7%, placebo adjusted)NCT02854605NCT03449446Tropifexor (LJN-452) (SM)Ph2Interim results of an ongoing Ph2 study were presented noting ALT reductions and modest liver fat content reduction at 60- and 90-μg doses, mild increase in LDL, and decrease in HDL. Increased pruritus incidence relative to placebo noted at 90-μg doseNCT02855164EDP-305 (SM)Ph2FGF19 increases and C4 decreases noted in Ph1. Increased incidence in Pruritus and decreased HDL (but no LDL increase) at 20-mg dose relative to placeboNCT02918929NCT03421431MET409 (SM)Ph1Ph1 ongoingNot postedTHR-β agonistMGL-3196 (SM)Ph2Reduction in liver fat content and ALT noted following 12 and 36 wk of administration. NASH w and ≥1-point improvements in fibrosis noted after 36 wk administration.NCT02912260VK2809 (SM)Ph2>50% relative reduction (placebo adjusted) in liver fat content noted at 10-mg daily dose. Increases in ALT noted in Ph1 and at early time points in Ph2, though ALT was not different from placebo after 12 wk administration. ALT reduction would have been expected given robust liver fat reductions.NCT02927184FGF peptide mimeticsFGF19NGM 282 (P)Ph257% and 45% relative reductions (placebo adjusted) in hepatic steatosis noted at 6 and 3-mg doses accompanied by improvements in ALT, AST, and C4. Increased incidence of injection site reactions and GI AEs noted in subjects who received MGM 282 vs placebo. Improvements in all components of NAS as well as fibrosis noted in non–placebo-controlled 12-wk exploratory study.NCT01943045NCT02443116FGF21BMS-986036 (P)Ph2Reductions in liver fat content accompanied by improvements in ALT, AST, Pro-C3, and MRE noted in 16 Ph2 studies. Improvements in cardio metabolic parameters (TG, LDL, HDL) also noted.NCT02413372β-Klotho/FGFR1c receptor agonistNGM313 (MK-3655)Ph1b proof of concept study in normal healthy overweight/obese shows reduction in liver fat contentNCT02708576NCT03298464Incretin therapiesGLP-1 mimeticsLiraglutide (P)Approved for T2D, exploratory studies for NASHImprovements in NASH resolution and fibrosis noted in NASH patients administered liraglutide vs placebo for 48 wk.NCT01237119Semaglutide (P)Approved for T2D, in Ph2 for NASHRobust improvements in glycemic control and body weight loss noted in both once-weekly and once-daily administered semaglutide. Ph2 biopsy study underwayNCT02970942DPP4 inhibitorSitagliptin (SM)Approved for T2D, exploratory studies for NASHSitagliptin showed no improvements in liver fat content, ALT, AST, and MRE vs placebo in a double-blinded, placebo-controlled study, though some earlier, small, open-label, or retrospective studies showed apparent improvements in liver enzymes and reduction in NASNCT01963845SGLT2 inhibitorsSGLT1/2 inhibitorLIK066Ph2Ph2 study in obese patients with NASH ongoingNCT03205150SGLT2 inhibitordapagliflozinPh3Ph3 planned to study efficacy and safety of dapagliflozin in NASHNCT03723252Other mechanisms of actionMPC inhibitorMSDC-0602K (SM)Ph2A press release from Cirius reported that statically significant reductions in ALT and AST were observed in an interim analysis on an ongoing Ph2b trialNCT02784444PXL065 (DRX-065) (SM)Ph1Ph1 study in healthy subjects ongoingNot postedACC, acetyl-CoA carboxylase; ALT, alanine aminotransferase; ASO, antisense oligonucleotide; AST, aspartate aminotransferase; DGAT, diacylglycerol O-acyltransferase; DNL, de novo lipogenesis; DPP4, •••; FAS, fatty acid synthase; FGF, fibroblast growth factor; FXR, Farnesoid X receptor; GLP-1, glucagon-like peptide-1; HDL, high-density lipoprotein; MPC, mitochondrial pyruvate carrier; MRE, •••; NAFLD, nonalcoholic fatty liver disease; NAS, Nonalcoholic Fatty Liver Disease Activity Score; NASH, nonalcoholic steatohepatitis; P, peptide or modified peptide; PBC, primary biliary cholangitis; PPAR, peroxisome proliferator-activated receptor; SGLT2, sodium glucose co-transporter 2; SM, small molecule; T2D, type 2 diabetes; TG, triglyceride; THR, thyroid hormone receptor. Open table in a new tab ACC, acetyl-CoA carboxylase; ALT, alanine aminotransferase; ASO, antisense oligonucleotide; AST, aspartate aminotransferase; DGAT, diacylglycerol O-acyltransferase; DNL, de novo lipogenesis; DPP4, •••; FAS, fatty acid synthase; FGF, fibroblast growth factor; FXR, Farnesoid X receptor; GLP-1, glucagon-like peptide-1; HDL, high-density lipoprotein; MPC, mitochondrial pyruvate carrier; MRE, •••; NAFLD, nonalcoholic fatty liver disease; NAS, Nonalcoholic Fatty Liver Disease Activity Score; NASH, nonalcoholic steatohepatitis; P, peptide or modified peptide; PBC, primary biliary cholangitis; PPAR, peroxisome proliferator-activated receptor; SGLT2, sodium glucose co-transporter 2; SM, small molecule; T2D, type 2 diabetes; TG, triglyceride; THR, thyroid hormone receptor. Over nutrition, accompanied by hyperinsulinemia and hyperglycemia, drives steatosis by promoting de novo lipogenesis (DNL). Lipogenic transcription factors including carbohydrate response element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c) are upregulated in rodent models, leading to increased expression of lipogenic genes and subsequent increased flux through acetyl-CoA carboxylase (ACC) and elevations in hepatic malonyl-CoA.24Hooper A.J. Adams L.A. Burnett J.R. Genetic determinants of hepatic steatosis in man.J Lipid Res. 2011; 52: 593-617Crossref PubMed Scopus (81) Google Scholar This leads to increased hepatic DNL and suppressed hepatic fatty acid oxidation which together promote steatosis (Figure 1).24Hooper A.J. Adams L.A. Burnett J.R. Genetic determinants of hepatic steatosis in man.J Lipid Res. 2011; 52: 593-617Crossref PubMed Scopus (81) Google Scholar Hepatic SREBP1c has also been reported to be upregulated in patients with NAFLD25Kohjima M. Enjoji M. Higuchi N. Kato M. Kotoh K. Yoshimoto T. Fujino T. Yada M. Yada R. Harada N. Takayanagi R. Nakamuta M. Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease.Int J Mol Med. 2007; 20: 351-358PubMed Google Scholar, 26Pettinelli P. Del Pozo T. Araya J. Rodrigo R. Araya A.V. Smok G. Csendes A. Gutierrez L. Rojas J. Korn O. Maluenda F. Diaz J.C. Rencoret G. Braghetto I. Castillo J. Poniachik J. Videla L.A. Enhancement in liver SREBP-1c/PPAR-alpha ratio and steatosis in obese patients: correlations with insulin resistance and n-3 long-chain polyunsaturated fatty acid depletion.Biochim Biophys Acta. 2009; 1792: 1080-1086Crossref PubMed Scopus (127) Google Scholar and elevated rates of hepatic DNL have been found to be a distinctive characteristic of NAFLD.27Lambert J.E. Ramos-Roman M.A. Browning J.D. Parks E.J. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease.Gastroenterology. 2014; 146: 726-735Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar Humans with elevated liver fat showed a >3-fold increase in hepatic DNL relative to subjects with normal liver fat, but differences between the groups were not detected in adipose free fatty acid (FFA) flux or in production of very low-density lipoprotein (VLDL) from FFAs.27Lambert J.E. Ramos-Roman M.A. Browning J.D. Parks E.J. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease.Gastroenterology. 2014; 146: 726-735Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar The observation that fructose consumption, which strongly promotes hepatic DNL,28Hudgins L.C. Parker T.S. Levine D.M. Hellerstein M.K. A dual sugar challenge test for lipogenic sensitivity to dietary fructose.J Clin Endocrinol Metab. 2011; 96: 861-868Crossref PubMed Scopus (66) Google Scholar is a risk factor for NAFLD29Abid A. Taha O. Nseir W. Farah R. Grosovski M. Assy N. Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome.J Hepatol. 2009; 51: 918-924Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, 30Ouyang X. Cirillo P. Sautin Y. McCall S. Bruchette J.L. Diehl A.M. Johnson R.J. Abdelmalek M.F. Fructose consumption as a risk factor for non-alcoholic fatty liver disease.J Hepatol. 2008; 48: 993-999Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar may further underscore the importance of DNL in this disease. Fructose-induced hepatic lipogenesis also likely contributes to the rise in rates of NAFLD. Fructose is a simple sugar found naturally in fruit and is a major component of sucrose (table sugar) and high-fructose corn syrup. Dietary trends in recent decades demonstrate a sharp increase in consumption of fructose and epidemiological studies have shown a strong correlation between consumption of fructose-sweetened beverages and risk for fatty liver.30Ouyang X. Cirillo P. Sautin Y. McCall S. Bruchette J.L. Diehl A.M. Johnson R.J. Abdelmalek M.F. Fructose consumption as a risk factor for non-alcoholic fatty liver disease.J Hepatol. 2008; 48: 993-999Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar, 31Herman M.A. Samuel V.T. The sweet path to metabolic demise: fructose and lipid synthesis.Trends Endocrinol Metab. 2016; 27: 719-730Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 32Lim J.S. Mietus-Snyder M. Valente A. Schwarz J.M. Lustig R.H. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome.Nat Rev Gastroenterol Hepatol. 2010; 7: 251-264Crossref PubMed Scopus (383) Google Scholar, 33Stanhope K.L. Schwarz J.M. Havel P.J. 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The sweet path to metabolic demise: fructose and lipid synthesis.Trends Endocrinol Metab. 2016; 27: 719-730Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar Thus, strategies aimed at directly inhibiting fructose metabolism (ie, ketohexokinase inhibition35Huard K. Ahn K. Amor P. Beebe D.A. Borzilleri K.A. Chrunyk B.A. Coffey S.B. Cong Y. Conn E.L. Culp J.S. Dowling M.S. Gorgoglione M.F. Gutierrez J.A. Knafels J.D. Lachapelle E.A. Pandit J. Parris K.D. Perez S. Pfefferkorn J.A. Price D.A. Raymer B. Ross T.T. Shavnya A. Smith A.C. Subashi T.A. Tesz G.J. Thuma B.A. Tu M. Weaver J.D. Weng Y. Withka J.M. Xing G. Magee T.V. Discovery of fragment-derived small molecules for in vivo inhibition of ketohexokinase (KHK).J Med Chem. 2017; 60: 7835-7849Crossref PubMed Scopus (3) Google Scholar or limiting fructose consumption in the diet) represent attractive therapeutic approaches for NAFLD and NASH. Emerging data also indicate that DNL may be important in regulating some inflammatory pathways in NASH. Berod et al36Berod L. Friedrich C. Nandan A. Freitag J. Hagemann S. Harmrolfs K. Sandouk A. Hesse C. Castro C.N. Bahre H. Tschirner S.K. Gorinski N. Gohmert M. Mayer C.T. Huehn J. Ponimaskin E. Abraham W.R. Muller R. Lochner M. Sparwasser T. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells.Nat Med. 2014; 20: 1327-1333Crossref PubMed Scopus (258) Google Scholar reported that proinflammatory interleukin-17 secreting T cells of the T helper 17 lineage show increased dependency on DNL to produce phospholipids for cellular membranes. In contrast, anti-inflammatory regulatory T cells (Treg) utilize exogenous fatty acids. Inhibition of DNL in primary T cells blunts formation of proinflammatory interleukin-17 secreting T cells of the T helper 17 lineage cells and promotes formation of anti-inflammatory Treg. Further, a higher frequency of Th17 cells in liver and an increase in the ratio of Th17 cells to Treg in peripheral blood and in liver marks progression from NAFLD to NASH in humans.37Rau M. Schilling A.K. Meertens J. Hering I. Weiss J. Jurowich C. Kudlich T. Hermanns H.M. Bantel H. Beyersdorf N. Geier A. Progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis is marked by a higher frequency of Th17 cells in the liver and an increased Th17/resting regulatory T cell ratio in peripheral blood and in the liver.J Immunol. 2016; 196: 97-105Crossref PubMed Scopus (0) Google Scholar Pharmacologic agents that inhibit DNL have potential to reduce steatosis and lipotoxicity. Inhibitors of the lipogenic enzymes ACC, fatty acid synthase (FAS), and diacylglycerol O-acyltransferase (DGAT) are in clinical development for NASH (Table 1). ACC catalyzes the first committed step in DNL, the production of malonyl-CoA though the adenosine triphosphate–dependent condensation of acetyl-CoA with carbonate.38Saggerson D. Malonyl-CoA, a key signaling molecule in mammalian cells.Annu Rev Nutr. 2008; 28: 253-272Crossref PubMed Scopus (137) Google Scholar Malonyl-CoA is also an allosteric inhibitor of
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