Failing FXR expression in the liver links aging to hepatic steatosis
Authors: Philippe Lefebvre, Bart Staels
Journal: Journal of Hepatology (2014)

Hepatic steatosis exacerbated by endoplasmic reticulum stress-mediated downregulation of FXR in aging miceJournal of HepatologyVol. 60Issue 4PreviewNon-alcoholic fatty liver disease (NAFLD) is characterized by an increase in hepatic triglyceride (TG) contents. The prevalence of NAFLD is increased with aging. However, the molecular mechanism for aging-induced fatty liver remains poorly understood. Full-Text PDF Aging is characterized, amongst other ailments, by an increased prevalence of symptoms of the metabolic syndrome such as elevated blood pressure, dyslipidemia and insulin resistance, which rise from 7% in the 20–29 year-old population to 44% in the 60–69 year-old population [[1]Alexander C.M. Landsman P.B. Grundy S.M. The influence of age and body mass index on the metabolic syndrome and its components.Diabetes Obes Metab. 2008; 10: 246-250Crossref PubMed Scopus (58) Google Scholar]. Excessive accumulation of fat in the liver, or steatosis, is a predictor of these metabolic alterations and is as such often considered as the hepatic manifestation of the metabolic syndrome. Ectopic fat accumulation as well as inappropriate lipid partitioning in the liver is believed to play a driving role in the etiology of insulin resistance [[2]Gaggini M. Morelli M. Buzzigoli E. DeFronzo R.A. Bugianesi E. Gastaldelli A. Non-alcoholic fatty liver disease [NAFLD] and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease.Nutrients. 2013; 5: 1544-1560Crossref PubMed Scopus (550) Google Scholar] and considered by many as the primary step in the development of non-alcoholic fatty liver disease (NAFLD). During the progression of NAFLD, simple steatosis evolves, in predisposed individuals, towards a condition termed non-alcoholic steatohepatitis (NASH), diagnosed as a combination of steatosis, inflammation and hepatocyte ballooning. Liver injury may worsen and progress to fibrosis and cirrhosis and eventually to hepatocellular carcinoma [[3]Levene A.P. Goldin R.D. The epidemiology, pathogenesis and histopathology of fatty liver disease.Histopathology. 2012; 61: 141-152Crossref PubMed Scopus (140) Google Scholar], conditions of unmet therapeutical need as liver transplantation is still the only curative option [[4]Charlton M. Evolving aspects of liver transplantation for nonalcoholic steatohepatitis.Curr Opin Organ Transplant. 2013; 18: 251-258Crossref PubMed Scopus (47) Google Scholar]. Multiple factors have been incriminated in the progression of NAFLD, such as excessive consumption of simple carbohydrates leading to enhanced hepatic lipogenesis, altered composition of the gut microbiome and aberrant immune-inflammatory responses, all of which interact with genetic factors [[5]Wree A. Broderick L. Canbay A. Hoffman H.M. Feldstein A.E. From NAFLD to NASH to cirrhosis-new insights into disease mechanisms.Nat Rev Gastroenterol Hepatol. 2013; 10: 627-636Crossref PubMed Scopus (426) Google Scholar]. Furthermore, NAFLD is a recognized independent risk factor for cardiovascular disease and type 2 diabetes mellitus [[6]Smith B.W. Adams L.A. Nonalcoholic fatty liver disease and diabetes mellitus: pathogenesis and treatment.Nat Rev Endocrinol. 2011; 7: 456-465Crossref PubMed Scopus (262) Google Scholar]. From a molecular perspective, several mechanisms have been proposed to explain the progression of NAFLD, the most common being the two-hit hypothesis [[7]Day C.P. James O.F. Steatohepatitis: a tale of two “hits”?.Gastroenterology. 1998; 114: 842-845Abstract Full Text Full Text PDF PubMed Scopus (3518) Google Scholar]. Whereas the second hit includes a variety of factors, such as hepatocyte senescence, oxidative stress, increased lipid peroxidation products, gut flora bio-products, or mitochondrial dysfunction resulting from a lipotoxic environment, the first hit is often considered to be a lipotoxic insult. Many of these alterations are accelerated by aging. Proper lipid homeostasis in the liver relies in large part on the physiological dynamics of subcellular lipid partitioning, lipid assembly and lipolysis of lipid droplets and lipid degradation via mitochondrial oxidation and lipid fluxes to the autophagic system. The proteasomal, lysosomal and autophagosome pathways are age-regulated pathways implicated in the control of lipid accumulation in the liver [8Xu X. Hueckstaedt L.K. Ren J. Deficiency of insulin-like growth factor 1 attenuates aging-induced changes in hepatic function: role of autophagy.J Hepatol. 2013; 59: 308-317Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 9Czaja M.J. Autophagy in health and disease 2. Regulation of lipid metabolism and storage by autophagy: pathophysiological implications.Am J Physiol Cell Physiol. 2010; 298: C973-C978Crossref PubMed Scopus (113) Google Scholar, 10Tomaru U. Takahashi S. Ishizu A. Miyatake Y. Gohda A. Suzuki S. et al.Decreased proteasomal activity causes age-related phenotypes and promotes the development of metabolic abnormalities.Am J Pathol. 2012; 180: 963-972Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar]. Interestingly, the global age-related changes in liver chromatin structure [[11]Moraes A.S. Guaraldo A.M. Mello M.L. Chromatin supraorganization and extensibility in mouse hepatocytes with development and aging.Cytometry A. 2007; 71: 28-37Crossref PubMed Scopus (26) Google Scholar] hint at alterations in epigenomic events, which are controlled by transcription factors and associated co-activating or co-repressing proteins. Accordingly, co-repressor-associated de-acetylases, such as Sirt1 and HDAC1, as well as the histone acetyl transferase p300 [12Jin J. Iakova P. Jiang Y. Medrano E.E. Timchenko N.A. The reduction of SIRT1 in livers of old mice leads to impaired body homeostasis and to inhibition of liver proliferation.Hepatology. 2011; 54: 989-998Crossref PubMed Scopus (77) Google Scholar, 13Minor R.K. Baur J.A. Gomes A.P. Ward T.M. Csiszar A. Mercken E.M. et al.SRT1720 improves survival and healthspan of obese mice.Sci Rep. 2011; 1 ([[email protected] Aug 18:70]): 70https://doi.org/10.1038/srep00070Crossref PubMed Scopus (234) Google Scholar, 14Jin J. Iakova P. Breaux M. Sullivan E. Jawanmardi N. Chen D. et al.Increased expression of enzymes of triglyceride synthesis is essential for the development of hepatic steatosis.Cell Rep. 2013; 3: 831-843Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar], all of which are involved in lipid homeostasis, display altered expression profiles in the aging liver. Furthermore, the expression levels of several nuclear receptors, many of which are involved in the control of metabolic adaptation to environmental stimuli, are affected in the liver of senescence-prone mice [15Erhuma A. Salter A.M. Sculley D.V. Langley-Evans S.C. Bennett A.J. Prenatal exposure to a low-protein diet programs disordered regulation of lipid metabolism in the aging rat.Am J Physiol Endocrinol Metab. 2007; 292: E1702-E1714Crossref PubMed Scopus (140) Google Scholar, 16Vila L. Roglans N. Alegret M. Camins A. Pallas M. Sanchez R.M. et al.Hypertriglyceridemia and hepatic steatosis in senescence-accelerated mouse associate to changes in lipid-related gene expression.J Gerontol A Biol Sci Med Sci. 2007; 62: 1219-1227Crossref PubMed Scopus (11) Google Scholar]. Amongst such nuclear receptors is the nuclear bile acid receptor FXR. FXR (NR1H4) regulates liver function by negatively interfering with bile acid synthesis through the SHP-LRH1 axis, with glycolysis through direct inhibition of ChREBP [[17]Caron S. Huaman S.C. Dehondt H. Ploton M. Briand O. Lien F. et al.Farnesoid X receptor inhibits the transcriptional activity of carbohydrate response element binding protein in human hepatocytes.Mol Cell Biol. 2013; 33: 2202-2211Crossref PubMed Scopus (100) Google Scholar] and with lipogenesis through the SHP-SREBP1c axis [[18]Lefebvre P. Cariou B. Lien F. Kuipers F. Staels B. Role of bile acids and bile acid receptors in metabolic regulation.Physiol Rev. 2009; 89: 147-191Crossref PubMed Scopus (1184) Google Scholar]. Together with the induction of PPARα expression, activation of hepatic FXR thus leads to reduced hepatic fatty acid and triglyceride synthesis and increased fatty acid oxidation. In line, FXR-deficient mice display a moderate steatosis. Xiong and collaborators report in this issue of the Journal of Hepatology a novel mechanism resulting in the decrease of FXR protein expression in the liver of aging C57BL/6 mice and show this favors age-induced steatosis. They further show that aging promotes endoplasmic reticulum (ER) stress, which can be alleviated by the treatment of aged mice with the chemical chaperones tauro-ursodeoxycholic acid (TUDCA), a hydrophilic bile acid derivative, or 4-phenylbutyrate (PBA), a compound chemically unrelated to TUDCA, and resulted in an increased expression of FXR. By contrast, administration of the ER stress-inducer tunicamycin led to a marked down-regulation of FXR. Using a combination of molecular approaches and JNK1-deficient mice, the authors showed that the down-regulation of FXR is the result of JNK1-mediated inhibition of HNF1α transcriptional activity. Since HNF1α is a known regulator of FXR gene transcription, the authors conclude that activation of the ER stress-JNK1-HNF1α signaling cascade is responsible for the down-regulation of FXR. This mechanism reinforces the idea of pharmacological activation of FXR as a possible therapeutic intervention in NAFLD patients, a hypothesis currently tested in a phase IIb trial with the bile acid derivative INT747, a potent FXR activator [[19]Mudaliar S. Henry R.R. Sanyal A.J. Morrow L. Marschall H.U. Kipnes M. et al.Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease.Gastroenterology. 2013; 145: 574-582Abstract Full Text Full Text PDF PubMed Scopus (695) Google Scholar]. The aging liver is also characterized by a significant loss in the regeneration capacity of hepatocytes as shown by a marked decrease in telomere length. Interestingly, FXR positively controls hepatic regeneration by directly stimulating Foxm1b expression [[20]Chen W.D. Wang Y.D. Zhang L. Shiah S. Wang M. Yang F. et al.Farnesoid X receptor alleviates age-related proliferation defects in regenerating mouse livers by activating forkhead box M1b transcription.Hepatology. 2010; 51: 953-962Crossref PubMed Scopus (143) Google Scholar], thus strengthening the potential role of FXR as a therapeutic target in liver diseases. The results presented by Xiong et al. further add to our understanding on the mechanisms of age-related progression of chronic liver diseases related to steatosis. However, inflammation, hepatocyte ballooning and especially fibrosis are major characteristics in the progression of NAFLD to a pathological condition. Whether activation of FXR directly acts on these two parameters is not yet fully understood, but deserves further investigation to fully appreciate the spectrum of the biological actions and potential pharmacological applications of FXR. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.