Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver

Santhosh Satapati, Blanka Kucejova, Joao A G Duarte, Justin A. Fletcher, Lacy Reynolds, Nishanth E. Sunny, Tianteng He, L. Arya Nair, Kenneth Livingston, Xiaorong Fu, Matthew E. Merritt, A. Dean Sherry, Craig R. Malloy, John M. Shelton, Jennifer Lambert, Elizabeth J. Parks, Ian Corbin, Mark A. Magnuson, Jeffrey D. Browning, Shawn C. Burgess

Research output: Contribution to journalArticle

146 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4447-4462
Number of pages16
JournalJournal of Clinical Investigation
Volume125
Issue number12
DOIs
StatePublished - Dec 1 2015

ASJC Scopus subject areas

  • Medicine(all)

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    Satapati, S., Kucejova, B., Duarte, J. A. G., Fletcher, J. A., Reynolds, L., Sunny, N. E., He, T., Arya Nair, L., Livingston, K., Fu, X., Merritt, M. E., Dean Sherry, A., Malloy, C. R., Shelton, J. M., Lambert, J., Parks, E. J., Corbin, I., Magnuson, M. A., Browning, J. D., & Burgess, S. C. (2015). Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver. Journal of Clinical Investigation, 125(12), 4447-4462. https://doi.org/10.1172/JCI82204