Editorial See corresponding article on page 130.
Retinoid X receptor: the forgotten partner in regulating lipid metabolism? Brent A Neuschwander-Tetri*
With the prevalence of nonalcoholic steatohepatitis (NASH)1 emerging in parallel with the epidemic of obesity and type 2 diabetes, cirrhosis caused by NASH has been projected to become the leading indication for liver transplantation over the next decade. For many reasons, implementing and sustaining lifestyle interventions are of limited effectiveness for NASH as they are for obesity and diabetes. We thus have a clear need for effective medications. Preventing or reversing NASH with targeted pharmacologic therapies requires an understanding of the underlying pathophysiology of this disease, and substantial progress has been made in this direction over the past 2 decades. The primary underlying problems are the oversupply of fatty acids in the liver or impaired disposal of fatty acids in hepatocytes, resulting in the generation of lipotoxic fatty acid derivatives that lead to cell injury, inflammation, and progressive liver fibrosis (1). The supply is driven by de novo lipogenesis within hepatocytes from excess carbohydrates, especially fructose, and the delivery of fatty acids to the liver from insulin-resistant adipose tissue. The disposal of fatty acids is primarily through oxidative metabolism by mitochondria or esterification to form triglyceride, which is secreted into the blood as VLDL. If the secretory capacity for VLDL from hepatocytes is overwhelmed, triglyceride can be stored temporarily in lipid droplets. Although the abundance of lipid droplets in hepatocytes was once thought to drive the pathogenesis of NASH, evidence shows that this is a relatively benign way to store fat and the accumulation of lipid droplets is generally more of an epiphenomenon than a cause of cellular injury. There are many potential modulating processes that influence whether lipotoxic liver injury occurs during the metabolism of an abundance of fatty acids, how severe the injury will be, and whether a fibrotic response will be elicited. Studies have shown contributory roles of the gut microbiome, various cytokines and adipokines, cholesterol, uric acid, iron, periodic hypoxia, industrial toxins, and a variety of other stresses. In addition, many genetic polymorphisms likely play predisposing or protective roles, but an understanding of which genes are involved and why is only in its infancy. In the context of identifying factors that might contribute to the pathogenesis of NASH, the study by Liu et al. (2) in this issue of the Journal shows that low concentrations of circulating retinoic acid (RA) are associated with more severe disease. The authors
report the results of an observational study conducted in China and found that people with nonalcoholic fatty liver disease have lower circulating RA concentrations than do normal controls. The differences were not trivial, with concentrations in those having severe NASH being less than half the concentrations in controls. In addition, the authors found that hepatic expression of the retinoid X receptor (RXR) was decreased in patients with NASH at the mRNA and protein levels, suggesting impaired signaling by RXR at multiple levels. Liu et al. (2) undertook their study of RA concentrations and RXR expression because ample animal evidence had shown that RXR, which is activated by RA and other lipids, has wide-ranging effects on virtually all aspects of the regulation of lipid metabolism (3). The nuclear receptors that regulate the genes responsible for fat metabolism throughout the body [i.e., peroxisome proliferator–activated receptor (PPAR) c, PPARa, PPARd, farnesoid X receptor (FXR), and liver X receptor (LXR)] are bound to their cognate DNA response elements mostly as heterodimers with RXR (4). The interaction of the 2 nuclear receptors in the heterodimer pair is considered “permissive,” meaning that the presence of ligand for both is not necessary, but when ligands for both receptors are present the resulting gene expression is greatly amplified. Much attention is now being focused on activating the partners of RXR that regulate lipid metabolism as treatments for NASH. The PIVENS (Pioglitazone versus Vitamin E in NASH Treatment) trial found that the PPARc ligand pioglitazone improved NASH in approximately half the patients receiving the drug (5), an effect that mechanistically may be related to improving adipose insulin sensitivity and decreasing the flow of fatty acids from adipose tissue to the liver by PPARc activation in adipose tissue (6). More recently, randomized controlled trials of an FXR agonist (7) and another with a dual PPARa/ PPARd agonist showed histologic benefits for treating NASH. However, the study by Liu et al. now raises the question of whether the benefit of the drugs tested in these large trials *To whom correspondence should be addressed. E-mail [email protected]. 1 Abbreviations used: FXR, farnesoid X receptor; LXR, liver X receptor; NASH, nonalcoholic steatohepatitis; PPAR, peroxisome proliferator–activated receptor; RA, retinoic acid; RXR, retinoid X receptor. First published online June 10, 2015; doi: 10.3945/ajcn.115.114330.
Am J Clin Nutr 2015;102:5–6. Printed in USA. Ó 2015 American Society for Nutrition
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Downloaded from ajcn.nutrition.org at NEW YORK UNIVERSITY BOBST LIBRARY on July 14, 2015
Division of Gastroenterology and Hepatology, St. Louis University School of Medicine, St. Louis, MO
6
EDITORIAL The author has served as a consultant to Nimbus Therapeutics, Bristol Myers Squibb, Janssen, Mitsubishi Tanabe, Conatus, and Scholar Rock.
REFERENCES 1. Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology 2010;52:774–88. 2. Liu Y, Chen H, Wang J, Zhou W, Sun R, Xia M. Association of serum retinoic acid with hepatic steatosis and liver injury in nonalcoholic fatty liver disease. Am J Clin Nutr 2015;102:130–7. 3. Wan YJ, An D, Cai Y, Repa JJ, Hung-Po Chen T, Flores M, Postic C, Magnuson MA, Chen J, Chien KR, et al. Hepatocyte-specific mutation establishes retinoid X receptor a as a heterodimeric integrator of multiple physiological processes in the liver. Mol Cell Biol 2000;20:4436–44. 4. Evans RM, Mangelsdorf DJ. Nuclear receptors, RXR, and the Big Bang. Cell 2014;157:255–66. 5. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362:1675–85. 6. Gastaldelli A, Harrison SA, Belfort-Aguilar R, Hardies LJ, Balas B, Schenker S, Cusi K. Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis. Hepatology 2009;50:1087–93. 7. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, Chalasani N, Dasarathy S, Diehl AM, Hameed B, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebocontrolled trial. Lancet 2015;385:956–65. 8. Lee Y-S, Jeong W-I. Retinoic acids and hepatic stellate cells in liver disease. J Gastroenterol Hepatol 2012;27(Suppl 2):75–9.
Downloaded from ajcn.nutrition.org at NEW YORK UNIVERSITY BOBST LIBRARY on July 14, 2015
could be increased by ensuring that patients receiving PPARc, FXR, or PPARa/PPARd ligands are not deficient in RA and, if so, if they would have additional benefit from concomitant treatment with a retinoid compound. The study raises additional questions that need to be answered. We don’t know why patients with NASH have low RA concentrations. The possibilities are many. Perhaps poor dietary habits with inadequate intake of retinoid-rich vegetables predispose to NASH, obesity, and low RA concentrations by multiple mechanisms so that the low RA concentrations are really a marker of poor dietary habits with inadequate micronutrients. Alternatively, retinol is stored in hepatic stellate cell lipid droplets. When these cells are stressed, as occurs in liver injury, the retinol is released from the droplets, oxidized to RA, and released. Perhaps with chronic low-grade liver injury, the stimulus to release RA outpaces the rate of replenishment (8). The question now is how do we use this new information? First, as proposed by the authors, the findings need to be replicated in a larger trial. We will then need to know if normalizing the retinoid status pharmacologically has beneficial or detrimental effects on lipid metabolism. Perhaps most importantly, we need to know if repletion of retinoids would have additive beneficial effects if combined with the PPARc, PPARa/PPARd, or FXR ligands. Like all good studies, the study finding of low RA concentrations raises more questions than it answers. We have work to do.
Retinoid X receptor: the forgotten partner in regulating lipid metabolism? Brent A Neuschwander-Tetri*
With the prevalence of nonalcoholic steatohepatitis (NASH)1 emerging in parallel with the epidemic of obesity and type 2 diabetes, cirrhosis caused by NASH has been projected to become the leading indication for liver transplantation over the next decade. For many reasons, implementing and sustaining lifestyle interventions are of limited effectiveness for NASH as they are for obesity and diabetes. We thus have a clear need for effective medications. Preventing or reversing NASH with targeted pharmacologic therapies requires an understanding of the underlying pathophysiology of this disease, and substantial progress has been made in this direction over the past 2 decades. The primary underlying problems are the oversupply of fatty acids in the liver or impaired disposal of fatty acids in hepatocytes, resulting in the generation of lipotoxic fatty acid derivatives that lead to cell injury, inflammation, and progressive liver fibrosis (1). The supply is driven by de novo lipogenesis within hepatocytes from excess carbohydrates, especially fructose, and the delivery of fatty acids to the liver from insulin-resistant adipose tissue. The disposal of fatty acids is primarily through oxidative metabolism by mitochondria or esterification to form triglyceride, which is secreted into the blood as VLDL. If the secretory capacity for VLDL from hepatocytes is overwhelmed, triglyceride can be stored temporarily in lipid droplets. Although the abundance of lipid droplets in hepatocytes was once thought to drive the pathogenesis of NASH, evidence shows that this is a relatively benign way to store fat and the accumulation of lipid droplets is generally more of an epiphenomenon than a cause of cellular injury. There are many potential modulating processes that influence whether lipotoxic liver injury occurs during the metabolism of an abundance of fatty acids, how severe the injury will be, and whether a fibrotic response will be elicited. Studies have shown contributory roles of the gut microbiome, various cytokines and adipokines, cholesterol, uric acid, iron, periodic hypoxia, industrial toxins, and a variety of other stresses. In addition, many genetic polymorphisms likely play predisposing or protective roles, but an understanding of which genes are involved and why is only in its infancy. In the context of identifying factors that might contribute to the pathogenesis of NASH, the study by Liu et al. (2) in this issue of the Journal shows that low concentrations of circulating retinoic acid (RA) are associated with more severe disease. The authors
report the results of an observational study conducted in China and found that people with nonalcoholic fatty liver disease have lower circulating RA concentrations than do normal controls. The differences were not trivial, with concentrations in those having severe NASH being less than half the concentrations in controls. In addition, the authors found that hepatic expression of the retinoid X receptor (RXR) was decreased in patients with NASH at the mRNA and protein levels, suggesting impaired signaling by RXR at multiple levels. Liu et al. (2) undertook their study of RA concentrations and RXR expression because ample animal evidence had shown that RXR, which is activated by RA and other lipids, has wide-ranging effects on virtually all aspects of the regulation of lipid metabolism (3). The nuclear receptors that regulate the genes responsible for fat metabolism throughout the body [i.e., peroxisome proliferator–activated receptor (PPAR) c, PPARa, PPARd, farnesoid X receptor (FXR), and liver X receptor (LXR)] are bound to their cognate DNA response elements mostly as heterodimers with RXR (4). The interaction of the 2 nuclear receptors in the heterodimer pair is considered “permissive,” meaning that the presence of ligand for both is not necessary, but when ligands for both receptors are present the resulting gene expression is greatly amplified. Much attention is now being focused on activating the partners of RXR that regulate lipid metabolism as treatments for NASH. The PIVENS (Pioglitazone versus Vitamin E in NASH Treatment) trial found that the PPARc ligand pioglitazone improved NASH in approximately half the patients receiving the drug (5), an effect that mechanistically may be related to improving adipose insulin sensitivity and decreasing the flow of fatty acids from adipose tissue to the liver by PPARc activation in adipose tissue (6). More recently, randomized controlled trials of an FXR agonist (7) and another with a dual PPARa/ PPARd agonist showed histologic benefits for treating NASH. However, the study by Liu et al. now raises the question of whether the benefit of the drugs tested in these large trials *To whom correspondence should be addressed. E-mail [email protected]. 1 Abbreviations used: FXR, farnesoid X receptor; LXR, liver X receptor; NASH, nonalcoholic steatohepatitis; PPAR, peroxisome proliferator–activated receptor; RA, retinoic acid; RXR, retinoid X receptor. First published online June 10, 2015; doi: 10.3945/ajcn.115.114330.
Am J Clin Nutr 2015;102:5–6. Printed in USA. Ó 2015 American Society for Nutrition
5
Downloaded from ajcn.nutrition.org at NEW YORK UNIVERSITY BOBST LIBRARY on July 14, 2015
Division of Gastroenterology and Hepatology, St. Louis University School of Medicine, St. Louis, MO
6
EDITORIAL The author has served as a consultant to Nimbus Therapeutics, Bristol Myers Squibb, Janssen, Mitsubishi Tanabe, Conatus, and Scholar Rock.
REFERENCES 1. Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology 2010;52:774–88. 2. Liu Y, Chen H, Wang J, Zhou W, Sun R, Xia M. Association of serum retinoic acid with hepatic steatosis and liver injury in nonalcoholic fatty liver disease. Am J Clin Nutr 2015;102:130–7. 3. Wan YJ, An D, Cai Y, Repa JJ, Hung-Po Chen T, Flores M, Postic C, Magnuson MA, Chen J, Chien KR, et al. Hepatocyte-specific mutation establishes retinoid X receptor a as a heterodimeric integrator of multiple physiological processes in the liver. Mol Cell Biol 2000;20:4436–44. 4. Evans RM, Mangelsdorf DJ. Nuclear receptors, RXR, and the Big Bang. Cell 2014;157:255–66. 5. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362:1675–85. 6. Gastaldelli A, Harrison SA, Belfort-Aguilar R, Hardies LJ, Balas B, Schenker S, Cusi K. Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis. Hepatology 2009;50:1087–93. 7. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, Chalasani N, Dasarathy S, Diehl AM, Hameed B, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebocontrolled trial. Lancet 2015;385:956–65. 8. Lee Y-S, Jeong W-I. Retinoic acids and hepatic stellate cells in liver disease. J Gastroenterol Hepatol 2012;27(Suppl 2):75–9.
Downloaded from ajcn.nutrition.org at NEW YORK UNIVERSITY BOBST LIBRARY on July 14, 2015
could be increased by ensuring that patients receiving PPARc, FXR, or PPARa/PPARd ligands are not deficient in RA and, if so, if they would have additional benefit from concomitant treatment with a retinoid compound. The study raises additional questions that need to be answered. We don’t know why patients with NASH have low RA concentrations. The possibilities are many. Perhaps poor dietary habits with inadequate intake of retinoid-rich vegetables predispose to NASH, obesity, and low RA concentrations by multiple mechanisms so that the low RA concentrations are really a marker of poor dietary habits with inadequate micronutrients. Alternatively, retinol is stored in hepatic stellate cell lipid droplets. When these cells are stressed, as occurs in liver injury, the retinol is released from the droplets, oxidized to RA, and released. Perhaps with chronic low-grade liver injury, the stimulus to release RA outpaces the rate of replenishment (8). The question now is how do we use this new information? First, as proposed by the authors, the findings need to be replicated in a larger trial. We will then need to know if normalizing the retinoid status pharmacologically has beneficial or detrimental effects on lipid metabolism. Perhaps most importantly, we need to know if repletion of retinoids would have additive beneficial effects if combined with the PPARc, PPARa/PPARd, or FXR ligands. Like all good studies, the study finding of low RA concentrations raises more questions than it answers. We have work to do.
