The role of hypoxia-inducible factor 1α in hepatic lipid metabolism

Chronic liver disease is a major public health problem with a high and increasing prevalence worldwide. In the progression of chronic liver disease, steatosis drives the progression of the disease to cirrhosis or even liver cancer. Hypoxia-inducible factor 1α (HIF-1α) is central to the regulation of hepatic lipid metabolism. HIF-1α upregulates the expression of genes related to lipid uptake and synthesis in the liver and downregulates the expression of lipid oxidation genes. Thus, it promotes intrahepatic lipid deposition. In addition, HIF-1α is expressed in white adipose tissue, where lipolysis releases free fatty acids (FFAs) into the blood. These circulating FFAs are taken up by the liver and accumulate in the liver. The expression of HIF-1α in the liver condenses bile and makes it easier to form gallstones. Contrary to the role of hepatic HIF-1α, intestinal HIF-1α expression can maintain a healthy microbiota and intestinal barrier. Thus, it plays a protective role against hepatic steatosis. This article aims to provide an overview of the current understanding of the role of HIF-1α in hepatic steatosis and to encourage the development of therapeutic agents associated with HIF-1α pathways. KEY MESSAGES: • Hepatic HIF-1α expression promotes lipid uptake and synthesis and reduces lipid oxidation leading to hepatic steatosis. • The expression of HIF-1α in the liver condenses bile and makes it easier to form gallstones. • Intestinal HIF-1α expression can maintain a healthy microbiota and intestinal barrier.