title: Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver.
abstract: Mitochondria are critical for respiration in all tissues; however, in liver, these organelles also accommodate high-capacity anaplerotic/cataplerotic pathways that are essential to gluconeogenesis and other biosynthetic activities. During nonalcoholic fatty liver disease (NAFLD), mitochondria also produce ROS that damage hepatocytes, trigger inflammation, and contribute to insulin resistance. Here, we provide several lines of evidence indicating that induction of biosynthesis through hepatic anaplerotic/cataplerotic pathways is energetically backed by elevated oxidative metabolism and hence contributes to oxidative stress and inflammation during NAFLD. First, in murine livers, elevation of fatty acid delivery not only induced oxidative metabolism, but also amplified anaplerosis/cataplerosis and caused a proportional rise in oxidative stress and inflammation. Second, loss of anaplerosis/cataplerosis via genetic knockdown of phosphoenolpyruvate carboxykinase 1 (Pck1) prevented fatty acid-induced rise in oxidative flux, oxidative stress, and inflammation. Flux appeared to be regulated by redox state, energy charge, and metabolite concentration, which may also amplify antioxidant pathways. Third, preventing elevated oxidative metabolism with metformin also normalized hepatic anaplerosis/cataplerosis and reduced markers of inflammation. Finally, independent histological grades in human NAFLD biopsies were proportional to oxidative flux. Thus, hepatic oxidative stress and inflammation are associated with elevated oxidative metabolism during an obesogenic diet, and this link may be provoked by increased work through anabolic pathways.
authors.forename: Santhosh
authors.initials: S
authors.lastname: Satapati
authors.forename: Blanka
authors.initials: B
authors.lastname: Kucejova
authors.forename: Joao A G
authors.initials: JA
authors.lastname: Duarte
authors.forename: Justin A
authors.initials: JA
authors.lastname: Fletcher
authors.forename: Lacy
authors.initials: L
authors.lastname: Reynolds
authors.forename: Nishanth E
authors.initials: NE
authors.lastname: Sunny
authors.forename: Tianteng
authors.initials: T
authors.lastname: He
authors.forename: L Arya
authors.initials: LA
authors.lastname: Nair
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Livingston
authors.forename: Kenneth
authors.initials: K
authors.lastname: Livingston
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Fu
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Merritt
authors.forename: A Dean
authors.initials: AD
authors.lastname: Sherry
authors.forename: Craig R
authors.initials: CR
authors.lastname: Malloy
authors.forename: John M
authors.initials: JM
authors.lastname: Shelton
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lambert
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Parks
authors.forename: Ian
authors.initials: I
authors.lastname: Corbin
authors.forename: Mark A
authors.initials: MA
authors.lastname: Magnuson
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Browning
authors.forename: Shawn C
authors.initials: SC
authors.lastname: Burgess
mesh_terms: D000818:Animals; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C582554:Pck1 protein, rat; D010729:Phosphoenolpyruvate Carboxykinase (GTP)