Year-end Sale % OFF 
Abstract
Background & AimsMolecular mechanisms by which hypoxia might contribute to hepatosteatosis, the earliest stage in non‐alcoholic fatty liver disease (NAFLD) pathogenesis, remain still to be elucidated. We aimed to assess the impact of hypoxia‐inducible factor 2α (HIF2α) on the fatty acid translocase CD36 expression and function in vivo and in vitro.MethodsCD36 expression and intracellular lipid content were determined in hypoxic hepatocytes, and in hypoxic CD36‐ or HIF2α ‐silenced human liver cells. Histological analysis, and HIF2α and CD36 expression were evaluated in livers from animals in which von Hippel‐Lindau (Vhl) gene is inactivated (Vhlf/f‐deficient mice), or both Vhl and Hif2a are simultaneously inactivated (Vhlf/fHif2α/f‐deficient mice), and from 33 biopsy‐proven NAFLD patients and 18 subjects with histologically normal liver.ResultsIn hypoxic hepatocytes, CD36 expression and intracellular lipid content were augmented. Noteworthy, CD36 knockdown significantly reduced lipid accumulation, and HIF2A gene silencing markedly reverted both hypoxia‐induced events in hypoxic liver cells. Moreover livers from Vhlf/f‐deficient mice showed histologic characteristics of non‐alcoholic steatohepatitis (NASH) and increased CD36 mRNA and protein amounts, whereas both significantly decreased and NASH features markedly ameliorated in Vhlf/fHif2αf/f‐deficient mice. In addition, both HIF2α and CD36 were significantly overexpressed within the liver of NAFLD patients and, interestingly, a significant positive correlation between hepatic transcript levels of CD36 and erythropoietin (EPO), a HIF2α ‐dependent gene target, was observed in NAFLD patients.ConclusionsThis study provides evidence that HIF2α drives lipid accumulation in human hepatocytes by upregulating CD36 expression and function, and could contribute to hepatosteatosis setup.
Highlights
This study demonstrates for the first time that hypoxia-inducible factor 2α (HIF2α) upregulates CD36 expression and function contributing to hepatosteatosis in hepatocytes, but it provides evidence suggesting that a HIF2α-induced CD36 upregulation could be operative in vivo and play a relevant role in non-alcoholic fatty liver disease (NAFLD) pathophysiology in humans, as we found a significant increase of both HIF2α and CD36 protein content, and an elevated mRNA levels of CD36 and EPO, being the latter a well-known surrogate marker of HIF2α activation, as well as a marked positive correlation between these genes, in the livers of NAFLD patients
Hepatic protein amounts of both CD36 and HIF2α were similar in non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) patients indicating that its hepatic expression remains largely stable during histological progression from NAFL to NASH
Our data strongly suggest that the HIF2α/CD36 pathway could have a pathogenic role in the phase of hepatosteatosis, but further investigation is needed for understanding in depth its impact on NASH progression
Summary
Overnutrition is a major contributor to the development of nonalcoholic fatty liver disease (NAFLD) because a high consumption of saturated fatty acids, cholesterol and fructose along with a low intake of polyunsaturated fatty acids, featuring NAFLD patients, alters hepatic lipid metabolism homeostasis leading to an excessive fat accumulation within the liver which activates inflammation, hepatocellular damage and fibrogenesis.[1,2] There is extensive clinical and experimental evidence indicating that chronic intermittent hypoxia, featuring a respiratory disorder of growing prevalence worldwide termed obstructive sleep apnoea, could contribute to the progression of NAFLD from simple steatosis, termed non-alcoholic fatty liver (NAFL) or hepatosteatosis, to non-alcoholic steatohepatitis (NASH),[3,4,5,6] the most clinically relevant form of NAFLD with a significant risk to progress into cirrhosis and hepatocellular carcinoma,[7,8] as well as increasing the cardiovascular morbidity and mortality and the incidence of extrahepatic cancers.[9,10]. The aim of the present study was to determine the impact of HIF2α on CD36 expression and function as well as on lipid content in hepatocytes submitted to hypoxic conditions, in livers from genetically-modified mice in which von Hippel-Lindau (Vhl) gene is inactivated (Vhlf/f-deficient mice), a murine experimental model which displays NAFLD features due to an overexpression of HIF1 and HIF2, in livers from mice in which both Vhl and Hif2a are simultaneously inactivated (Vhlf/ fHif2αf/f-deficient mice), and in livers from patients with biopsy-proven NAFLD
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
