title: Hypoxia-regulated mechanisms in the pathogenesis of obesity and non-alcoholic fatty liver disease.
abstract: The pandemic rise in obesity has resulted in an increased incidence of metabolic complications. Non-alcoholic fatty liver disease is the hepatic manifestation of the metabolic syndrome and has become the most common chronic liver disease in large parts of the world. The adipose tissue expansion and hepatic fat accumulation characteristics of these disorders compromise local oxygen homeostasis. The resultant tissue hypoxia induces adaptive responses to restore oxygenation and tissue metabolism and cell survival. Hypoxia-inducible factors (HIFs) function as master regulators of this hypoxia adaptive response, and are in turn hydroxylated by prolyl hydroxylases (PHDs). PHDs are the main cellular oxygen sensors and regulate HIF proteasomal degradation in an oxygen-dependent manner. HIFs and PHDs are implicated in numerous physiological and pathological conditions. Extensive research using genetic models has revealed that hypoxia signaling is also a key mechanism in adipose tissue dysfunction, leading to adipose tissue fibrosis, inflammation and insulin resistance. Moreover, hypoxia affects liver lipid metabolism and deranges hepatic lipid accumulation. This review summarizes the molecular mechanisms through which the hypoxia adaptive response affects adipocyte and hepatic metabolism, and the therapeutic possibilities of modulating HIFs and PHDs in obesity and fatty liver disease.
authors.affiliation: Department of Gastroenterology and Hepatology, Ghent University Hospital, De Pintelaan 185, 1K12IE, 9000, Ghent, Belgium. sander.lefere@ugent.be.
authors.forename: Sander
authors.initials: S
authors.lastname: Lefere
authors.affiliation: Department of Gastroenterology and Hepatology, Ghent University Hospital, De Pintelaan 185, 1K12IE, 9000, Ghent, Belgium.|Department of Gastroenterology and Hepatology, Maria Middelares Hospital, Ghent, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Van Steenkiste
authors.affiliation: Department of Gastroenterology and Hepatology, Ghent University Hospital, De Pintelaan 185, 1K12IE, 9000, Ghent, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Verhelst
authors.affiliation: Department of Gastroenterology and Hepatology, Ghent University Hospital, De Pintelaan 185, 1K12IE, 9000, Ghent, Belgium.
authors.forename: Hans
authors.initials: H
authors.lastname: Van Vlierberghe
authors.affiliation: Department of Gastroenterology and Hepatology, Ghent University Hospital, De Pintelaan 185, 1K12IE, 9000, Ghent, Belgium.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Devisscher
authors.affiliation: Department of Gastroenterology and Hepatology, Ghent University Hospital, De Pintelaan 185, 1K12IE, 9000, Ghent, Belgium.
authors.forename: Anja
authors.initials: A
authors.lastname: Geerts
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D050356:Lipid Metabolism / Q000502:physiology; D018919:Neovascularization, Physiologic; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism / Q000473:pathology*; D009765:Obesity / Q000378:metabolism / Q000473:pathology*; D010100:Oxygen / Q000378:metabolism; D064828:Prolyl Hydroxylases / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D010100:Oxygen; D064828:Prolyl Hydroxylases
keywords: Angiogenesis; Hypoxia; Hypoxia inducible factor; Lipid metabolism; Obesity; Oxygen homeostasis