Dietary Oxysterol, 7-Ketocholesterol Accelerates Hepatic Lipid Accumulation and Macrophage Infiltration in Obese Mice.

Jiuyang Chang,Masafumi Ono,Shizuya Yamashita,Makoto Nishida,Katsunao Tanaka,Ayami Saga,Masahiro Koseki,Toshiji Saibara,Masumi Asaji,Yoshihiro Kamada,Yinghong Zhu,Hiroyasu Inui,Tohru Ohama,Yasushi Sakata,Ikuyo Ichi,Tomoaki Higo,Kotaro Kanno,Takeshi Okada,Daisuke Okuzaki

doi:10.3389/fendo.2020.614692

Abstract

Non-alcoholic fatty liver disease is strongly associated with obese and type 2 diabetes. It has been reported that an oxidized cholesterol, 7-ketocholesterol (7KC), might cause inflammatory response in macrophages and plasma 7KC concentration were higher in patients with cardiovascular diseases or diabetes. Therefore, we have decided to test whether small amount of 7KC in diet might induce hepatic steatosis and inflammation in two types of obese models. We found that addition of 0.01% 7KC either in chow diet (CD, regular chow diet with 1% cholesterol) or western type diet (WD, high fat diet with 1% cholesterol) accelerated hepatic neutral lipid accumulation by Oil Red O staining. Importantly, by lipid extraction analysis, it has been recognized that triglyceride rather than cholesterol species was significantly accumulated in CD+7KC compared to CD as well as in WD+7KC compared to WD. Immunostaining revealed that macrophages infiltration was increased in CD+7KC compared to CD, and also in WD+7KC compared to WD. These phenotypes were accompanied by inducing inflammatory response and downregulating fatty acid oxidation. Furthermore, RNA sequence analysis demonstrated that 7KC reduced expression of genes which related to autophagy process. Levels of LC3-II protein were decreased in WD+7KC compared to WD. Similarly, we have confirmed the effect of 7KC on acceleration of steatohepatitis in db/db mice model. Collectively, our study has demonstrated that small amount of dietary 7KC contributed to accelerate hepatic steatosis and inflammation in obese mice models.

Highlights

Obesity is a complex disorder that has been a worldwide health problem for individuals as well as the society [1]
There were no differences of total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), non-HDL-C, or triglycerides in mice fed CD ± 7KC or WD ± 7KC (Figure 1E)
Oxysterols are categorized to two types, endogenous and exogenous sterols

Summary

Introduction

Obesity is a complex disorder that has been a worldwide health problem for individuals as well as the society [1]. The incident rate of Non-alcoholic fatty liver disease (NAFLD) is increasing and strongly associated with the patient’s background, such as obesity as well as type 2 diabetes mellitus (T2DM) [2,3,4]. NAFLD could be categorized into non-alcoholic fatty liver (NAFL) with simple steatosis or non-alcoholic steatohepatitis (NASH) which is accompanied with steatosis, inflammation, and fibrosis [5]. It is clinically important to distinguish two types of disease because the existence of inflammation could link to hepatic steatosis as well as systemic inflammatory disorders. A couple of studies have demonstrated that the presence of NAFLD was associated with higher incident ratio of atherosclerotic cardiovascular diseases (CVD) [6, 7]. There is a growing evidence that diet can affect the pathophysiology of NAFLD as well as CVD [9,10,11,12,13]

Methods

Results

Conclusion