Abstract

Both iron and lipids are involved in the progression of alcoholic fatty liver disease (AFLD), but the interaction between iron and lipids in AFLD is unclear. Here, we tested the hypothesis that iron regulates the expression of genes involved in lipid metabolism through iron regulatory proteins (IRPs), which interact with the iron-responsive elements (IREs) in the untranslated regions (UTRs) of genes, resulting in lipid accumulation. Using "RNA structure software", we predicted the mRNA secondary structures of more than 100 genes involved in lipid metabolism to investigate whether the IRE structure exists in novel mRNAs. Cholesterol 7α-hydroxylase (Cyp7a1) has an IRE-like stem-loop, a noncanonical IRE structure, in its 3'-UTR. Cyp7a1 expression can be regulated by in vivo and in vitro iron treatment. In addition, the noncanonical IRE motif can efficiently bind both to IRP1 and IRP2. The results indicate that hepatic iron overloading in AFLD mice decreased Cyp7a1 expression and resulted in cholesterol accumulation, providing a new mechanism of iron-regulated gene transcription and translation through the interaction between iron and a noncanonical IRE structure in Cyp7a1 mRNA. This finding has significant implications in studying a proposed mechanism for the regulation of cholesterol homeostasis by an Fe/IRP/noncanonical IRE axis.

Highlights

  • Both iron and lipids are involved in the progression of alcoholic fatty liver disease (AFLD), but the interaction between iron and lipids in AFLD is unclear

  • 9-month-old alcohol-treated mice showed no significant change in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), LDH, and TG, while cholesterol was slightly elevated in serum, but not statistically significantly different

  • We present data indicating a correlation between the hepatic iron content and lipid metabolism in alcohol-induced hepatic steatosis using a mouse model

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Summary

Introduction

Both iron and lipids are involved in the progression of alcoholic fatty liver disease (AFLD), but the interaction between iron and lipids in AFLD is unclear. The results indicate that hepatic iron overloading in AFLD mice decreased Cyp7a1 expression and resulted in cholesterol accumulation, providing a new mechanism of iron-regulated gene transcription and translation through the interaction between iron and a noncanonical IRE structure in Cyp7a1 mRNA. This finding has significant implications in studying a proposed mechanism for the regulation of cholesterol homeostasis by an Fe/IRP/noncanonical IRE axis.—Liang, H., H. Iron is an essential element for living organisms that plays a vital role in many physiological events Proteins, such as hemoglobin, may contain iron or iron-sulfur clusters in the prosthetic form.

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