Abstract
BackgroundThe 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.MethodsNAFLD 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.ResultsHFD 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 hypoxia-induced factor 1α and 2α, while neither lipotoxicity- nor hypoxia- induced hepatic steatosis was affected when HIF was knocked down.ConclusionsHFD 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.
Highlights
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
A growing number of studies have linked obstructive sleep apnea syndrome (OSAS) with NAFLD, by showing that OSAS patients predisposes to the development of NAFLD from pediatrics to the aged, and the mainly relevant is the burden of nocturnal hypoxia independently of BMI and diabetic status [6]
high-fat diet (HFD) feeding induced hepatic steatosis and provoked hepatic hypoxia in mice Mice were fed on HFD for 7 days, representing an acute effect, and 8 weeks, representing a chronic effect respectively
Summary
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. 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. A growing number of studies have linked obstructive sleep apnea syndrome (OSAS) with NAFLD, by showing that OSAS patients predisposes to the development of NAFLD from pediatrics to the aged, and the mainly relevant is the burden of nocturnal hypoxia independently of BMI and diabetic status [6]. OSAS, characterized by partial or total obstruction of the upper respiratory tract in sleep, represents a situation of intermittent hypoxia [7]. Blood TG levels raised in a young group of newcomers to altitude after being exposed chronically for 8 months [8], and twofold increase of hepatic triglycerides was observed in the chronic hypoxia rats [9]
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