Low-ω3 Fatty Acid and Soy Protein Attenuate Alcohol-Induced Fatty Liver and Injury by Regulating the Opposing Lipid Oxidation and Lipogenic Signaling Pathways.

Karina Reyes-Gordillo,Mamatha Garige,Ravi Varatharajalu,Leslie C Leckey,Ruchi Shah,M Raj Lakshman

doi:10.1155/2016/1840513

Abstract

Chronic ethanol-induced downregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1β) affect hepatic lipid oxidation and lipogenesis, respectively, leading to fatty liver injury. Low-ω3 fatty acid (Low-ω3FA) that primarily regulates PGC1α and soy protein (SP) that seems to have its major regulatory effect on PGC1β were evaluated for their protective effects against ethanol-induced hepatosteatosis in rats fed with Lieber-deCarli control or ethanol liquid diets with high or low ω3FA fish oil and soy protein. Low-ω3FA and SP opposed the actions of chronic ethanol by reducing serum and liver lipids with concomitant decreased fatty liver. They also prevented the downregulation of hepatic Sirtuin 1 (SIRT1) and PGC1α and their target fatty acid oxidation pathway genes and attenuated the upregulation of hepatic PGC1β and sterol regulatory element-binding protein 1c (SREBP1c) and their target lipogenic pathway genes via the phosphorylation of 5′ adenosine monophosphate-activated protein kinase (AMPK). Thus, these two novel modulators attenuate ethanol-induced hepatosteatosis and consequent liver injury potentially by regulating the two opposing lipid oxidation and lipogenic pathways.

Highlights

Alcohol liver disease is a major cause of morbidity and mortality, affecting millions world-wide [1]
You et al [16] and Lieber et al [41] have elegantly shown that both long chain and medium chain saturated fatty acids in the diet restore the expressions of silence regulator gene 1 (SIRT1) and PGC1α that are downregulated by long chain polyunsaturated fatty acids (PUFA) in chronic ethanol-fed animals
While the inability of these studies to show chronic ethanol-mediated upregulation of sterol regulatory element-binding proteins (SREBPs)-1c-mediated lipogenic pathway may be due to different dietary fat compositions compared to the present study, we consistently find that the upregulation of this pathway with the high-ω3FA diet was markedly attenuated by low-ω3FA diet

Summary

Introduction

Alcohol liver disease is a major cause of morbidity and mortality, affecting millions world-wide [1]. Transcriptional coactivators peroxisome proliferator receptor coactivator 1 alpha (PGC1α) and peroxisome proliferator receptor coactivator 1 beta (PGC1β) as well as sterol regulatory element-binding proteins (SREBPs) play vital roles in regulating the lipid oxidizing and lipogenic genes and thereby control the progression of hepatosteatosis and the consequent onset of fibrosis and other forms of liver injury [5, 6]. PGC1α regulates lipid oxidation pathway genes via PPARα and PGC1β regulates lipogenic pathway genes via the sterol regulatory elementbinding proteins SREB1a, SREB1c, and SREBP2 [11]. Any modulator that can either activate PGC1α via the interplay between SIRT1 and histone acetyltransferase (HAT) or inactivate PGC1β/SREBP1c should be beneficial in preventing alcoholic hepatosteatosis and consequent liver injury

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Conclusion