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World J Gastroenterol. Nov 7, 2014; 20(41): 15087-15097
Published online Nov 7, 2014. doi: 10.3748/wjg.v20.i41.15087
Hypoxia and fatty liver
Tomohiro Suzuki, Satoko Shinjo, Takatomo Arai, Mai Kanai, Nobuhito Goda
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
Author contributions: Suzuki T and Goda N designed and wrote the paper; Shinjo S, Arai T and Kanai M wrote the paper and discussed the body of the paper with Suzuki T and Goda N.
Supported by Grant from Waseda University (in part); a Grant For Special Research Projects from the MEXT-Supported Program for the Strategic Research Foundation at Private; and a Grant-in-Aid for Scientific Research (C) from MEXT
Correspondence to: Nobuhito Goda, MD, PhD, Department of Life Science and Medical BioScience, Waseda University School of Advanced Science and Engineering, TWIns 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan. goda@waseda.jp
Telephone: +81-3-53697319 Fax: +81-3-53697319
Received: October 25, 2013
Revised: February 14, 2014
Accepted: May 28, 2014
Published online: November 7, 2014
Processing time: 381 Days and 3.5 Hours
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: Hypoxia; Fatty liver disease; Hypoxia-inducible factor; Lipid metabolism; Obstructive sleep apnea

Core tip: Hypoxia occurs in the development and progression of fatty liver disease. Recent reports have shed light on the pathological significance of hypoxia inducible factors (HIFs), master regulators of the hypoxic response, with regard to their regulation of lipid metabolism in context- and isoform-dependent manners. In this review, we summarize recent findings on the various roles of HIF-dependent regulation in fatty liver disease.