Higd1a Protects Cells from Lipotoxicity under High-Fat Exposure.

Tong Li,Yong Zhang,Yang Gao,Qi-Chang Zheng,Wen-Jing Xian,Shuai Jiang,Qi-Hong Yu

doi:10.1155/2019/6051262

Abstract

Hypoxia-inducible gene domain family member 1A (Higd1a) has recently been reported to protect cells from hypoxia by helping to maintain normal mitochondrial function. The potential induction of Higd1a under high-fat exposure and whether it could protect cells from oxidative stress attracted our attention. Initially, 0.4 mM oleic acid and 0.2 mM palmitate were added to the growth media of HepG2 and LO2 cells for 72 hours. We discovered increased Higd1a expression, and knocking down Higd1a impaired mitochondrial transmembrane potential and induced cell apoptosis. We then identified that elevated reactive oxygen species (ROS) is responsible for increased Higd1a expression. Furthermore, we found that ROS promoted Higd1a expression by upregulating HIF-1a and PGC-1a expressions, and these two proteins could exert synergistic effects in inducing Higd1a expression. Taken together, these data suggest that Higd1a plays positive roles in protecting cells from oxidative stress, and ROS could induce Higd1a expression by upregulating PGC-1a and HIF-1a expressions.

Highlights

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases and is characterized by a wide range of alterations, including simple steatosis at early stages and steatohepatitis in advanced stages, in which fatty liver is accompanied by inflammation, hepatocyte ballooning, liver fibrosis, and disrupted glucose homeostasis and insulin resistance [1,2,3]
These results indicated that the expression of Hypoxia-inducible gene domain family member 1A (Higd1a) could be induced under high-fat exposure
We found that Higd1a mRNA and protein expression were decreased if PGC-1a was knocked down before cells were treated with FFAs (Figures 6(c) and 6(d)), whereas expression was increased if PGC-1a was overexpressed (Figures 6(e) and 6(f))

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases and is characterized by a wide range of alterations, including simple steatosis at early stages and steatohepatitis in advanced stages, in which fatty liver is accompanied by inflammation, hepatocyte ballooning, liver fibrosis, and disrupted glucose homeostasis and insulin resistance [1,2,3]. In NAFLD patients, the rates of fatty acid oxidation (FAO) exceed the tricarboxylic acid cycle (TCA) capacity, resulting in mitochondrial fatty acid overload and leading to incomplete FAO and accumulation of reactive oxygen species (ROS) that contribute to mitochondria dysfunction and cell damage [6, 7]. Impaired mitochondrial β-oxidation and defective mitochondrial respiratory chain subsequently contribute to hepatic steatosis [8, 9]. Protecting mitochondria from oxidative stress is one of the key aspects in treating NAFLD

Methods

Results

Conclusion