ChREBP in NASH – A liver transcription factor comes in from the cold
Authors: Michael R. Charlton
Journal: Journal of Hepatology (2013)

COMMENTARY ON: The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans. Benhamed F, Denechaud PD, Lemoine M, Robichon C, Moldes M, Bertrand-Michel J, Ratziu V, Serfaty L, Housset C, Capeau J, Girard J, Guillou H, Postic C. J Clin Invest 2012 Jun 1;122(6):2176–94. Copyright (2012). Abstract reprinted with permission from the American Society for Clinical Investigation. http://www.ncbi.nlm.nih.gov/pubmed/22546860 Abstract: Nonalcoholic fatty liver disease (NAFLD) is associated with all features of the metabolic syndrome. Although deposition of excess triglycerides within liver cells, a hallmark of NAFLD, is associated with a loss of insulin sensitivity, it is not clear which cellular abnormality arises first. We have explored this in mice overexpressing carbohydrate responsive element-binding protein (ChREBP). On a standard diet, mice overexpressing ChREBP remained insulin sensitive, despite increased expression of genes involved in lipogenesis/fatty acid esterification and resultant hepatic steatosis (simple fatty liver). Lipidomic analysis revealed that the steatosis was associated with increased accumulation of monounsaturated fatty acids (MUFAs). In primary cultures of mouse hepatocytes, ChREBP overexpression induced expression of stearoyl-CoA desaturase 1 (Scd1), the enzyme responsible for the conversion of saturated fatty acids (SFAs) into MUFAs. SFA impairment of insulin-responsive Akt phosphorylation was therefore rescued by the elevation of Scd1 levels upon ChREBP overexpression, whereas pharmacological or shRNA-mediated reduction of Scd1 activity decreased the beneficial effect of ChREBP on Akt phosphorylation. Importantly, ChREBP-overexpressing mice fed a high-fat diet showed normal insulin levels and improved insulin signaling and glucose tolerance compared with controls, despite having greater hepatic steatosis. Finally, ChREBP expression in liver biopsies from patients with nonalcoholic steatohepatitis was increased when steatosis was greater than 50% and decreased in the presence of severe insulin resistance. Together, these results demonstrate that increased ChREBP can dissociate hepatic steatosis from insulin resistance, with beneficial effects on both glucose and lipid metabolism. The rise of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) as an important etiology of liver disease has been remarkable. Querying PubMed in preparation for writing this commentary revealed that a total of four articles were published regarding NAFLD or NASH in 1992. In 2012 the number was over 400. In the United States, which has been at the crest of the global wave of obesity and metabolic syndrome, NASH is already the third most common indication for liver transplantation and is on a trajectory to become the most common [[1]Charlton M.R. Burns J.M. Pedersen R.A. Watt K.D. Heimbach J.K. Dierkhising R.A. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States.Gastroenterology. 2011; 141: 1249-1253Abstract Full Text Full Text PDF PubMed Scopus (881) Google Scholar]. The scale of the health burden of NAFLD is likely to increase in parallel with continued increases in the prevalence and severity of obesity. Despite the logarithmic increase in interest and consequences, we understand surprisingly little about the pathobiology of NAFLD and there are, as yet, no approved pharmacotherapies for this condition. A key facet of the epidemiology of NAFLD is that the majority of patients with obesity do not have NASH and a majority of patients with NASH do not have evidence of progressive fibrosis [[8]Williams C.D. Stengel J. Asike M.I. Torres D.M. Shaw J. Contreras M. et al.Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study.Gastroenterology. 2011; 140: 124-131Abstract Full Text Full Text PDF PubMed Scopus (1673) Google Scholar]. Although genetic factors, such as PNPLA3 genotype [[6]Romeo S. Kozlitina J. Xing C. Pertsemlidis A. Cox D. Pennacchio L.A. et al.Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.Nat Genet. 2008; 40: 1461-1465Crossref PubMed Scopus (2398) Google Scholar], and intestinal flora [[7]Spencer M.D. Hamp T.J. Reid R.W. Fischer L.M. Zeisel S.H. Fodor A.A. Association between composition of the human gastrointestinal microbiome and development of fatty liver with choline deficiency.Gastroenterology. 2011; 140: 976-986Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar] may contribute to the histological severity of NAFLD, the predictivity of PNPLA3 genotype and intestinal microbiome composition for severity of liver disease is small. Understanding the basis of the histological diversity of NAFLD will be central to improving our ability to diagnose and treat NAFLD. This will require a more granular understanding of the interplay between nutrition and organ specific metabolism. The article by Benhamed et al., in the Journal of Clinical Investigation provides welcome new insight into some of the most basic aspects of NAFLD and metabolic syndrome. The net accumulation of triglycerides within the liver in the context of chronic overnutrition is substantially mediated by the glucose stimulated activation of the liver transcription factor carbohydrate responsive element-binding protein (ChREBP) via induction of L-pyruvate kinase (L-PK) [[4]Ma L. Tsatsos N.G. Towle H.C. Direct role of ChREBP.Mlx in regulating hepatic glucose-responsive genes.J Biol Chem. 2005; 280: 12019-12027Crossref PubMed Scopus (145) Google Scholar]. Results of studies of the role and impact of ChREBP in glucose and lipid metabolism have been confusing, with global ChREBP deficiency resulting in insulin resistance in one murine model [[3]Iizuka K. Bruick R.K. Liang G. Horton J.D. Uyeda K. Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis.Proc Natl Acad Sci U S A. 2004; 101: 7281-7286Crossref PubMed Scopus (600) Google Scholar] vs. improved hepatic steatosis and insulin resistance in another [[2]Dentin R. Benhamed F. Hainault I. Fauveau V. Foufelle F. Dyck J.R. et al.Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice.Diabetes. 2006; 55: 2159-2170Crossref PubMed Scopus (340) Google Scholar]. Benhamed et al., hypothesized that these opposite phenotypes may be on the basis of the fact that ChREBP controls both glycolysis and lipogenesis and that the beneficial effect of ChREBP deficiency may only be apparent in the context of lipid overload. In order to test this hypothesis, the authors conducted an elegant series of experiments that should begin to fundamentally change the way we think of hepatic lipid and carbohydrate metabolism. The first important observation is that, on a standard diet, mice overexpressing ChREBP remain insulin sensitive despite increased lipogenesis/fatty acid esterification and resultant hepatic steatosis. Triglyceride accumulation and steatosis thus do not inevitably cause insulin resistance. The second important observation is that ChREBP-overexpressing mice fed a high-fat diet showed normal insulin levels and improved insulin signaling and glucose tolerance compared with controls despite having greater hepatic steatosis. This effect seems to be mediated by ChREBP modifying the MUFA/SFA balance in favor of MUFA. Together these findings provide new evidence that increased ChREBP can dissociate hepatic steatosis from insulin resistance, with beneficial effects on both glucose and lipid metabolism. The authors’ observations that ChREBP expression in liver biopsies from patients with NASH was relatively more abundant when steatosis was greater than 50%, and relatively less abundant in the presence of severe insulin resistance, supports this conclusion. The authors also provide novel mechanistic insight into ChREBP action through the identification of the lipogenic stearoyl-CoA desaturase (SCD1), which introduces a cis double bond in the Δ9 position of saturated 16- and 18-carbon fatty acids acyl-CoA substrates, as a key ChREBP target gene and likely effector of the beneficial effects of ChREBP expression. There are several important implications to this work. The most obvious is that the concept that ChREBP expression promotes insulin resistance and deleterious hepatic fat accumulation should be reconsidered. Indeed, the results reported by Benhamed et al. suggest that ChREBP activation might be explored as a potential therapeutic target in NAFLD and metabolic syndrome (Fig. 1 summarizes likely effects of ChREBP activation). The recent report that ChREBP greatly amplifies the glucose effect on beta cell proliferation [[5]Metukuri M.R. Zhang P.L. Basantani M.K. Chin C. Stamateris R.E. Alonso L.C. et al.ChREBP mediates glucose-stimulated pancreatic beta-cell proliferation.Diabetes. 2012; 61: 2004-2015Crossref PubMed Scopus (89) Google Scholar], increases the theoretical potential of ChREBP as a novel drug target. The results of Benhamed et al. also contribute to the rationale for changing how we think of “insulin sensitivity”. Insulin has complex and diverse effects on protein metabolism (primarily inhibits protein degradation but also has differential effects on protein synthesis), carbohydrate metabolism, and lipid metabolism. Clearly, the effects of insulin on carbohydrate and lipid metabolism can be dissociated and should be considered as distinct facets of insulin biology. Finally, we are overdue to reduce the use of the term high fat diet (HFD), particularly when referring to studies of NAFLD and NASH. When it comes to dietary fat, Benhamed et al. have highlighted the fact that composition is critical. Based on these results a HFD rich in oleic acid, for example, might be expected to enhance ChREBP expression, with subsequently favorable changes in hepatic lipid abundance and composition, and enhance carbohydrate insulin sensitivity. A diet relatively rich in saturated fats or cholesterol might be predicted to have the opposite effects. The article by Benhamed et al. has limitations, e.g., the applicability of adenoviral and in vitro studies to the complex human condition. Taken as a whole, however, this work is likely to be a landmark. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.