Ceramide as a mediator of non-alcoholic Fatty liver disease and associated atherosclerosis.

Takhar Kasumov,Xiuli Liu,Kailash Gulshan,Ling Li,Arthur Mccullough,Min Li,Belinda Willard,Jonathan D Smith,Stephen Previs,John P Kirwan,Yanqiao Zhang

doi:10.1371/journal.pone.0126910

Takhar Kasumov, Xiuli Liu + Show 9 more

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https://doi.org/10.1371/journal.pone.0126910

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Journal: PloS one	Publication Date: May 20, 2015
Citations: 167	License type: CC BY 4.0

Affiliation: Cleveland Clinic, Case Western Reserve University

Abstract

Cardiovascular disease (CVD) is a serious comorbidity in nonalcoholic fatty liver disease (NAFLD). Since plasma ceramides are increased in NAFLD and sphingomyelin, a ceramide metabolite, is an independent risk factor for CVD, the role of ceramides in dyslipidemia was assessed using LDLR-/- mice, a diet-induced model of NAFLD and atherosclerosis. Mice were fed a standard or Western diet (WD), with or without myriocin, an inhibitor of ceramide synthesis. Hepatic and plasma ceramides were profiled and lipid and lipoprotein kinetics were quantified. Hepatic and intestinal expression of genes and proteins involved in insulin, lipid and lipoprotein metabolism were also determined. WD caused hepatic oxidative stress, inflammation, apoptosis, increased hepatic long-chain ceramides associated with apoptosis (C16 and C18) and decreased very-long-chain ceramide C24 involved in insulin signaling. The plasma ratio of ApoB/ApoA1 (proteins of VLDL/LDL and HDL) was increased 2-fold due to increased ApoB production. Myriocin reduced hepatic and plasma ceramides and sphingomyelin, and decreased atherosclerosis, hepatic steatosis, fibrosis, and apoptosis without any effect on oxidative stress. These changes were associated with decreased lipogenesis, ApoB production and increased HDL turnover. Thus, modulation of ceramide synthesis may lead to the development of novel strategies for the treatment of both NAFLD and its associated atherosclerosis.

Highlights

nonalcoholic fatty liver disease (NAFLD) can progress from steatosis alone to non-alcoholic steatohepatitis (NASH) and to, cirrhosis
We have shown that the decrease in plasma ceramides in morbidly obese patients after bariatric surgery coincided with decreased ApoB levels, a reduced ApoB/ApoA1 ratio and a reduction in the overall cardiovascular disease (CVD) risk, suggesting that in addition to regulating HDL metabolism sphingolipids may contribute to atherosclerosis through their effect on ApoB metabolism [20]
Our results show that these changes in part may be related to (i) reduced hepatic lipogenesis and ApoB production, (ii) increased HDL turnover and expression of genes involved in reverse cholesterol transport” (RCT) (iii) and decreased absorption of dietary fatty acids and cholesterol

Summary

Introduction

NAFLD can progress from steatosis alone to non-alcoholic steatohepatitis (NASH) and to, cirrhosis. Despite these adverse hepatic outcomes, cardiovascular disease (CVD) is the major cause of death in these patients. Ceramide as a Mediator of NAFLD and Atherosclerosis It is unclear whether NAFLD is merely a marker of CVD risk, or a mediator that promotes a proatherogenic and inflammatory state. In NAFLD, chronic insulin resistance stimulates the overproduction of triglyceride-rich VLDL, which alters HDL composition through the actions of cholesterol ester transfer protein and hepatic lipase (HL) that leads to formation of small dense HDL particles prone to degradation [3]. The ApoB/ ApoAI ratio is considered a stronger predictor of CVD than triglycerides and cholesterol [6]

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