Induction of Liver Steatosis in BAP31-Deficient Mice Burdened with Tunicamycin-Induced Endoplasmic Reticulum Stress.

Zhenhua Wu,Fan Yang,Xiaoyu Sun,Shan Jiang,Jialin Xu

doi:10.3390/ijms19082291

Abstract

Endoplasmic reticulum (ER) stress is highly associated with liver steatosis. B-cell receptor-associated protein 31 (BAP31) has been reported to be involved in ER homeostasis, and plays key roles in hepatic lipid metabolism in high-fat diet-induced obese mice. However, whether BAP31 modulates hepatic lipid metabolism via regulating ER stress is still uncertain. In this study, wild-type and liver-specific BAP31-depleted mice were administrated with ER stress activator of Tunicamycin, the markers of ER stress, liver steatosis, and the underlying molecular mechanisms were determined. BAP31 deficiency increased Tunicamycin-induced hepatic lipid accumulation, aggravated liver dysfunction, and increased the mRNA levels of ER stress markers, including glucose-regulated protein 78 (GRP78), X-box binding protein 1 (XBP1), inositol-requiring protein-1α (IRE1α) and C/EBP homologous protein (CHOP), thus promoting ER stress in vivo and in vitro. Hepatic lipid export via very low-density lipoprotein (VLDL) secretion was impaired in BAP31-depleted mice, accompanied by reduced Apolipoprotein B (APOB) and microsomal triglyceride transfer protein (MTTP) expression. Exogenous lipid clearance was also inhibited, along with impaired gene expression related to fatty acid transportation and fatty acid β-oxidation. Finally, BAP31 deficiency increased Tunicamycin-induced hepatic inflammatory response. These results demonstrate that BAP31 deficiency increased Tunicamycin-induced ER stress, impaired VLDL secretion and exogenous lipid clearance, and reduced fatty acid β-oxidation, which eventually resulted in liver steatosis.

Highlights

Nonalcoholic fatty liver disease (NAFLD) refers to a wide spectrum of hepatic pathology, ranging from a simple liver steatosis (>5% of an intrahepatic accumulation of fat) to steatohepatitis [1]
We reported that B-cell receptor-associated protein 31 (BAP31) deficiency in hepatocytes increased Endoplasmic reticulum (ER) stress when burdened with Tm, increased Tm-induced liver dysfunction and hepatic inflammation, reduced very low-density lipoprotein (VLDL) secretion and lipid clearance, decreased the gene expression related to fatty acid oxidation, and eventually increased hepatic lipid accumulation
This study reveals the links among BAP31, ER stress, and liver steatosis, and points to the protective roles of BAP31 in the development of fatty liver disease

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) refers to a wide spectrum of hepatic pathology, ranging from a simple liver steatosis (>5% of an intrahepatic accumulation of fat) to steatohepatitis [1]. NAFLD is the most common liver disorder in Western industrialized countries, with an estimated prevalence rate up to 25% worldwide and 35% in the United States [2,3]. Over 64 million people are projected to have NAFLD in the United States, with annual medical costs of about $103 billion ($1613 per patient). About 52 million people in Germany, France, Italy and the United Kingdom are supposed to have NAFLD, with annual cost of €35 billion (from €354 to €1.163 per patient) [4]. There is an urgent need to understand the pathogenesis of liver steatosis regarding ER stress modulation and to identify new therapeutic molecular targets

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Conclusion