Hypoxia and fatty liver.
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.
Tomohiro Suzuki, Satoko Shinjo, Takatomo Arai, Mai Kanai, Nobuhito Goda, Department of Life Science and Medical BioScience, Waseda University School of Advanced Science and Engineering, Tokyo 162-8480, Japan.
Tomohiro
T
Suzuki
Tomohiro Suzuki, Satoko Shinjo, Takatomo Arai, Mai Kanai, Nobuhito Goda, Department of Life Science and Medical BioScience, Waseda University School of Advanced Science and Engineering, Tokyo 162-8480, Japan.
Satoko
S
Shinjo
Tomohiro Suzuki, Satoko Shinjo, Takatomo Arai, Mai Kanai, Nobuhito Goda, Department of Life Science and Medical BioScience, Waseda University School of Advanced Science and Engineering, Tokyo 162-8480, Japan.
Takatomo
T
Arai
Tomohiro Suzuki, Satoko Shinjo, Takatomo Arai, Mai Kanai, Nobuhito Goda, Department of Life Science and Medical BioScience, Waseda University School of Advanced Science and Engineering, Tokyo 162-8480, Japan.
Mai
M
Kanai
Tomohiro Suzuki, Satoko Shinjo, Takatomo Arai, Mai Kanai, Nobuhito Goda, Department of Life Science and Medical BioScience, Waseda University School of Advanced Science and Engineering, Tokyo 162-8480, Japan.
Nobuhito
N
Goda
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D005234:Fatty Liver / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000150:complications / Q000175:diagnosis / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000150:complications / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D012097:Repressor Proteins; D012307:Risk Factors; D015398:Signal Transduction; D020181:Sleep Apnea, Obstructive / Q000150:complications / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen; D012097:Repressor Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C116973:HIF3A protein, human
Fatty liver disease; Hypoxia; Hypoxia-inducible factor; Lipid metabolism; Obstructive sleep apnea