Hypoxia and fatty liver

Abstract

The liver is a central organ that metabolizes excessive nutrients for storage in the form of glycogen and lipids and supplies energy-producing substrates to the peripheral tissues to maintain their function, even under starved conditions. These processes require a considerable amount of oxygen, which causes a steep oxygen gradient throughout the hepatic lobules. Alcohol consumption and/or excessive food intake can alter the hepatic metabolic balance drastically, which can precipitate fatty liver disease, a major cause of chronic liver diseases worldwide, ranging from simple steatosis, through steatohepatitis and hepatic fibrosis, to liver cirrhosis. Altered hepatic metabolism and tissue remodeling in fatty liver disease further disrupt hepatic oxygen homeostasis, resulting in severe liver hypoxia. As master regulators of adaptive responses to hypoxic stress, hypoxia-inducible factors (HIFs) modulate various cellular and organ functions, including erythropoiesis, angiogenesis, metabolic demand, and cell survival, by activating their target genes during fetal development and also in many disease conditions such as cancer, heart failure, and diabetes. In the past decade, it has become clear that HIFs serve as key factors in the regulation of lipid metabolism and fatty liver formation. This review discusses the molecular mechanisms by which hypoxia and HIFs regulate lipid metabolism in the development and progression of fatty liver disease.

Keywords: Fatty liver disease; Hypoxia; Hypoxia-inducible factor; Lipid metabolism; Obstructive sleep apnea.

Figure 1

Regulation of hypoxia-inducible factors under normal and low oxygen concentrations. Under normoxia conditions, hypoxia-inducible factor α (HIF-α) is hydroxylated at specific proline residues in an oxygen-dependent manner, ubiquitylated by von Hippel-Lindau (VHL) protein (pVHL), and, subsequently, degraded by the proteasome. Under hypoxia conditions, stabilized HIF-α translocates to the nucleus and binds aryl hydrocarbon receptor nuclear translocator (ARNT) to activate its target genes. PHD: Prolyl hydroxylase domain; HRE: Hypoxia-response element.

Figure 2

Hypoxia-inducible factors regulate hepatic lipid metabolism. HIF-2 promotes lipid accumulation mainly by preventing mitochondrial β-oxidation and promoting lipid droplet formation. In contrast, HIF-1 suppresses lipid accumulation by inhibiting de novo lipogenesis. HIF-1 also promotes lipid storage and lipid export. HIF: Hypoxia-inducible factor; FA: Fatty acids; TG: Triglycerides.

Figure 3

Distinct regulations of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α under intermittent hypoxia conditions. ROS and Ca²⁺ play crucial roles in the regulation of HIF activity in response to intermittent hypoxia, which results in the activation of HIF-1 and suppression of HIF-2. IH: Intermittent hypoxia; OSA: Obstructive sleep apnea; NADPH: Nicotinamide adenine dinucleotide phosphate; PKC: Protein kinase C; mTOR: Mammalian target of rapamycin; CBP: CREB-binding protein; PHD: Prolyl hydroxylase domain; HIF: Hypoxia-inducible factor.