In Steatotic Cells, ATP-Citrate Lyase mRNA Is Efficiently Translated through a Cap-Independent Mechanism, Contributing to the Stimulation of De Novo Lipogenesis.

Luisa Siculella,Gabriele V. Gnoni,Fabrizio Damiano,Mariangela Testini,Laura Giannotti

doi:10.3390/ijms21041206

Luisa Siculella, Gabriele V. Gnoni + Show 3 more

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https://doi.org/10.3390/ijms21041206

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Abstract

Non-alcoholic fatty liver disease (NAFLD) is a chronic disease in which excessive amount of lipids is accumulated as droplets in hepatocytes. Recently, cumulative evidences suggested that a sustained de novo lipogenesis can play an important role in NAFLD. Dysregulated expression of lipogenic genes, including ATP-citrate lyase (ACLY), has been found in liver diseases associated with lipid accumulation. ACLY is a ubiquitous cytosolic enzyme positioned at the intersection of nutrients catabolism and cholesterol and fatty acid biosyntheses. In the present study, the molecular mechanism of ACLY expression in a cell model of steatosis has been reported. We identified an internal ribosome entry site (IRES) in the 5′ untranslated region of the ACLY mRNA, that can support an efficient mRNA translation through a Cap-independent mechanism. In steatotic HepG2 cells, ACLY expression was up-regulated through IRES-mediated translation. Since it has been demonstrated that lipid accumulation in cells induces endoplasmic reticulum (ER) stress, the involvement of this cellular pathway in the translational regulation of ACLY has been also evaluated. Our results showed that ACLY expression was increased in ER-stressed cells, through IRES-mediated translation of ACLY mRNA. A potential role of the Cap-independent translation of ACLY in NAFLD has been discussed.

Highlights

Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of hepatic disorders, ranging from simple fatty liver to non-alcoholic steatohepatitis (NASH), characterized by inflammation and hepatocytic injury, i.e., cell degeneration and necroapoptosis [1]
In this study we investigated the regulation of ATP-citrate lyase (ACLY) expression in an in vitro model of hepatic steatosis, represented by HepG2 cells treated with a mixture of palmitic and oleic fatty acids
We showed that accumulation of lipids stimulates the expression of ACLY in HepG2 cells at translational level, through an internal ribosome entry site (IRES) located in the 5 untranslated region (5 UTR) of ACLY mRNA

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of hepatic disorders, ranging from simple fatty liver (non-alcoholic fatty liver, NAFL) to non-alcoholic steatohepatitis (NASH), characterized by inflammation and hepatocytic injury, i.e., cell degeneration and necroapoptosis [1]. In NAFLD, triglycerides are accumulated and stored in the cytoplasm of hepatocytes in the form of lipid droplets, giving origin mainly to macrovesicular steatosis. This pathology is closely associated with obesity, type 2 diabetes, and insulin resistance (IR). Dietary chylomicron remnants and lipolysis from adipose tissue are the major sources of fatty acids for lipid accumulation in NAFLD. Hepatic de novo lipogenesis (DNL) has not been considered as a relevant cause of steatosis.

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