Background & Aims: Estrogen participates in the control of energy homeostasis and lipid metabolism. However the role of hepatic estrogen receptor alpha (ER alpha) in triglyceride (TG) homeostasis remains poorly understood. This study aims to investigate the roles of estrogen and ER alpha in the regulation of hepatic TG metabolism.Methods: Liver TG metabolism was analyzed in female mice with ovariectomy or tamoxifen treatment, and in hepatic ER alpha knockdown or overexpression. Phenotypes and expression of genes were compared in male and female mice with farnesoid X receptor deficiency. The mechanism of ER alpha in the regulation of small heterodimer partner (SHP) expression was further investigated.Results: Female mice receiving ovariectomy or tamoxifen treatment exhibited hepatic TG accumulation. Ablation of ER alpha using adenoviral shRNA markedly increased hepatic TG accumulation, while overexpression of ER alpha ameliorated hepatosteatosis in obese mice. At the molecular level, estrogen upregulated hepatic SHP expression through binding to its proximal promoter. In addition, the roles of estrogen were largely blunted in mice with SHP deficiency.Conclusion: These findings reveal a novel role of estrogen in improving hepatosteatosis through upregulation of SHP expression. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Hepatosteatosis is characterized by an aberrant accumulation of triglycerides in the liver; however, the factors that drive obesity-induced fatty liver remain largely unknown. Here, we demonstrated that the secreted cell adhesion protein periostin is markedly upregulated in livers of obese rodents and humans. Notably, overexpression of periostin in the livers of WT mice promoted hepatic steatosis and hypertriglyceridemia. Conversely, both genetic ablation of periostin and administration of a periostin-neutralizing antibody dramatically improved hepatosteatosis and hypertriglyceridemia in obese mice. Overexpression of periostin resulted in reduced expression of peroxisome proliferator-activated receptor α (PPARα), a master regulator of fatty acid oxidation, and activation of the JNK signaling pathway. In mouse primary hepatocytes, inhibition of α6β4 integrin prevented activation of JNK and suppression of PPARα in response to periostin. Periostin-dependent activation of JNK resulted in activation of c-Jun, which prevented RORα binding and transactional activation at the Ppara promoter. Together, these results identify a periostin-dependent pathway that mediates obesity-induced hepatosteatosis.

Hepatosteatosis is characterized by an aberrant accumulation of triglycerides in the liver; however, the factors that drive obesity-induced fatty liver remain largely unknown. Here, we demonstrated that the secreted cell adhesion protein periostin is markedly upregulated in livers of obese rodents and humans. Notably, overexpression of periostin in the livers of WT mice promoted hepatic steatosis and hypertriglyceridemia. Conversely, both genetic ablation of periostin and administration of a periostin-neutralizing antibody dramatically improved hepatosteatosis and hypertriglyceridemia in obese mice. Overexpression of periostin resulted in reduced expression of peroxisome proliferator-activated receptor a (PPAR alpha), a master regulator of fatty acid oxidation, and activation of the INK signaling pathway. In mouse primary hepatocytes, inhibition of alpha 6 beta 4 integrin prevented activation of JNK and suppression of PPARa in response to periostin. Periostin-dependent activation of JNK resulted in activation of c-Jun, which prevented ROR alpha binding and transactional activation at the Ppara promoter. Together, these results identify a periostin-dependent pathway that mediates obesity-induced hepatosteatosis.

BACKGROUND & AIMS:Non-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. METHODS:Hepatic TG contents and gene expression profiles were analyzed in body weight-matched young (2 months), middle (8 months) and old (18 months) C57BL/6 mice. Endoplasmic reticulum (ER) stress and farnesoid X receptor (FXR) expression were examined. The mechanism of ER stress activation in the regulation of FXR expression was further investigated. RESULTS:In the present study, we found that TG was markedly accumulated and lipogenic genes were up-regulated in the liver of C57BL/6 mice aged 18 months. FXR, a key regulator of hepatic lipid metabolism was down-regulated in these old mice. At molecular levels, ER stress was activated in old mice and repressed FXR expression through inhibition of hepatocyte nuclear factor 1 alpha (HNF1α) transcriptional activity. CONCLUSIONS:Our findings demonstrate that FXR down-regulation plays a critical role in aging-induced fatty liver.