HFD and HFD-provoked hepatic hypoxia act as reciprocal causation for NAFLD via HIF-independent signaling
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RESEARCH ARTICLE
HFD and HFD‑provoked hepatic hypoxia act as reciprocal causation for NAFLD via HIF‑independent signaling Xiaofang Zhang1,2,3, Caoxin Huang1,2,3, Xuejun Li1,2,3,4, Zhaoshui Shangguan5, Wenjing Wei1,2,3, Suhuan Liu5, Shuyu Yang1,2,3* and Yijie Liu6*
Abstract Background: The occurrence of non-alcoholic fatty liver disease (NAFLD) is found to be higher in patients with obstructive sleep apnea (OSA), which is characterized by intermittent hypoxia. Activation of hypoxia-inducible factors has been shown in the development and progression of NAFLD, implying a cause and effects relationship between NAFLD and hypoxia. The present study was designed to investigate the interaction of lipotoxicity and hypoxia in the pathogenesis of NAFLD using mice model with high-fat diet (HFD) feeding or hypoxic treatment. Methods: NAFLD model was induced in mice by HFD feeding, and in cultured primary hepatocytes by administration of palmitate acid. Mouse hypoxic model was produced by placing the mice in a Animal incubator with oxygen concentration at 75% followed by a 21% oxygen supplement. Hypoxic condition was mimicked by treating the hepatocytes with cobalt chloride (CoCl2) or 1% oxygen supply. Pimonidazole assay was conducted to evaluate hypoxia. Lipid metabolic genes were measured by real-time polymerase-chain reaction. HIF-1α and HIF-2α genes were silenced by siRNA. Results: HFD feeding and palmitate acid treatment provoked severe hepatic hypoxia along with TG accumulation in mice and in cultured primary hepatocytes respectively. Conversely, hypoxia induced hepatic TG accumulation in mice and in cultured primary hepatocytes. Hypoxic treatment inhibited the expression of lipolytic genes, while increased the expression of lipogenicgenes in mice. Although both lipotoxicity and hypoxia could activate hepatic hypoxiainduced factor 1α and 2α, while neither lipotoxicity- nor hypoxia- induced hepatic steatosis was affected when HIF was knocked down. Conclusions: HFD resulted in hepatic TG accumulation and concomitant hypoxia. Conversely, hypoxia induced hepatic TG accumulation in mice and in cultured heptocytes. Thus lipotoxicity and hypoxia might work as reciprocal causation and orchestrate to promote the development of NAFLD. Keywords: NAFLD, Hypoxia, HIF, Steatosis
*Correspondence: [email protected]; [email protected] 1 Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, 55 Zhenhai Road, Xiamen 361003, China 6 Siming Branch, The First Affiliated Hospital of Xiamen University, 55 Zhenhai Road, Xiamen 361003, China Full list of author information is available at the end of the article
Background Non-alcoholic fatty liver disease (NAFLD) is increasingly recognized as one of the most common liver disease, which frequently progresses into nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma [1, 2]. Due to the lack of efficient treatment except life style intervention, NAFLD is associated with high morbidity rate affecting more than 30% of the adults and 10
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