Soy protein reduces hepatic lipotoxicity in hyperinsulinemic obese Zucker fa/fa rats

Armando R Tovar,Ivan Torre-Villalvazo,Melissa Ochoa,Ana L Elías,Victor Ortíz,Carlos A Aguilar-Salinas,Nimbe Torres

doi:10.1194/jlr.m500067-jlr200

Abstract

Hepatic steatosis is commonly present during the development of insulin resistance, and it is a clear sign of lipotoxicity attributable in part to an accelerated lipogenesis. There is evidence that a soy protein diet prevents the overexpression of hepatic sterol-regulatory element binding protein-1 (SREBP-1), decreasing lipid accumulation. Therefore, the aim of the present work was to study whether a soy protein diet may prevent the development of fatty liver through the regulation of transcription factors involved in lipid metabolism in hyperinsulinemic and hyperleptinemic Zucker obese fa/fa rats. Serum and hepatic cholesterol and triglyceride levels, as well as VLDL-triglyceride and LDL-cholesterol, were significantly lower in rats fed soy protein than in rats fed a casein diet for 160 days. The reduction in hepatic cholesterol was associated with a low expression of liver X receptor-alpha and its target genes, 7-alpha hydroxylase and ABCA1. Soy protein also decreased the expression of SREBP-1 and several of its target genes, FAS, stearoyl-CoA desaturase-1, and delta5 and delta6 desaturases, decreasing lipogenesis even in the presence of hyperinsulinemia. Reduction in SREBP-1 was not associated with the presence of soy isoflavones. Finally, soy protein reduced SREBP-1 expression in adipocytes, preventing hypertrophy, which also helps prevent the development of hepatic lipotoxicity.

Highlights

Hepatic steatosis is commonly present during the development of insulin resistance, and it is a clear sign of lipotoxicity attributable in part to an accelerated lipogenesis
Several lines of evidence indicate that fatty liver in insulin-resistant states is caused by the activation of the sterolregulatory element binding protein-1c (SREBP-1c), which is increased in response to high insulin levels even in resistant states [3]
As many as 40% of type 2 diabetics or ZDF obese fa/fa rats accumulate significant amounts of triglycerides in adipose tissue and in liver. This leads to hepatic steatosis or “fatty liver,” a condition that progresses to hepatic fibrosis and cirrhosis in a subset of individuals [2]

Summary

Introduction

Hepatic steatosis is commonly present during the development of insulin resistance, and it is a clear sign of lipotoxicity attributable in part to an accelerated lipogenesis. The aim of the present work was to study whether a soy protein diet may prevent the development of fatty liver through the regulation of transcription factors involved in lipid metabolism in hyperinsulinemic and hyperleptinemic Zucker obese fa/fa rats. Several lines of evidence indicate that fatty liver in insulin-resistant states is caused by the activation of the sterolregulatory element binding protein-1c (SREBP-1c), which is increased in response to high insulin levels even in resistant states [3]. Studies have demonstrated that the addition of the synthetic LXR ligand T0901317 increased the expression of SREBP-1c [9], indicating that these nuclear receptors provide interregulatory control of the cholesterol and fatty acid metabolism. Short-term ingestion of soy protein leads to lower serum insulin concentration compared with rats fed casein, and this response is accompanied by a small increase in hepatic SREBP-1 mRNA [13].

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Conclusion