Role of HO-1 against Saturated Fatty Acid-Induced Oxidative Stress in Hepatocytes.

Noriyoshi Ogino,Narufumi Suganuma,Masashi Kusanaga,Masaru Harada,Shinji Oe,Masamitsu Eitoku,Shihona Ogino,Koichiro Miyagawa,Yuichi Honma,Yuki Matsuura-Harada,Keiki Ogino,Kenjiro Nagaoka

doi:10.3390/nu13030993

Abstract

Increased circulating levels of free fatty acids, especially saturated ones, are involved in disease progression in the non-alcoholic fatty liver. Although the mechanism of saturated fatty acid-induced toxicity in the liver is not fully understood, oxidative stress may be deeply involved. We examined the effect of increased palmitic acid, the most common saturated fatty acid in the blood, on the liver of BALB/c mice via tail vein injection with palmitate. After 24 h, among several anti-oxidative stress response genes, only heme oxygenase-1 (HO-1) was significantly upregulated in palmitate-injected mice compared with that in vehicle-injected mice. Elevation of HO-1 mRNA was also observed in the fatty liver of high-fat-diet-fed mice. To further investigate the role of HO-1 on palmitic acid-induced oxidative stress, in vitro experiments were performed to expose palmitate to HepG2 cells. SiRNA-mediated knockdown of HO-1 significantly increased the oxidative stress induced by palmitate, whereas pre-treatment with SnCl2, a well-known HO-1 inducer, significantly decreased it. Moreover, SB203580, a selective p38 inhibitor, reduced HO-1 mRNA expression and increased palmitate-induced oxidative stress in HepG2 cells. These results suggest that the HO-1-mediated anti-oxidative stress compensatory reaction plays an essential role against saturated fatty acid-induced lipotoxicity in the liver.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disease worldwide [1]
Considering these results, the fact that a single palmitic acid administration into the blood of Balb-c mice did not increase alanine transaminase (ALT) despite the oxidative stress in the liver might be due to the response of increased heme oxygenase-1 (HO-1)
The elevation of ALT levels in mice fed an High-fat diets (HFDs) for 12 weeks might mean that HO-1 could not fully respond to oxidative stress caused by sustained lipid-overload

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disease worldwide [1]. When the same experiment was examined in the presence of oleic acid (the most abundant unsaturated fatty acids) to approximate in vivo conditions, the cytotoxicity of palmitic acid was almost attenuated. Based on these results, it was necessary to explore the effects of elevated blood levels of palmitic acid on the liver under in vivo conditions where various types of lipids are present. Total free fatty acid concentrations in the blood have been reported to increase transiently in postprandial condition or by lipolysis in adipose tissue [13], there are few in vivo experiments on hepatotoxicity when palmitic acid is increased

Methods

Results

Conclusion