Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver
Santhosh Satapati, … , Jeffrey D. Browning, Shawn C. Burgess
Santhosh Satapati, … , Jeffrey D. Browning, Shawn C. Burgess
Published November 16, 2015
Citation Information: J Clin Invest. 2015;125(12):4447-4462. https://doi.org/10.1172/JCI82204.
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Research Article Metabolism

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

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

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Figure 1

Propionate tracers do not perturb basal hepatic flux.

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Propionate tracers do not perturb basal hepatic flux. Propionate (0.8 μm...
Propionate (0.8 μmol•min–1) did not alter (A) glucose production or (B) O2 consumption in livers perfused with gluconeogenic substrates and NEFA (n = 4). Propionate infusion (0.5 μmol•min–1) into conscious and unrestrained mice did not alter (C) endogenous glucose production (n = 3) and (D) resulted in tracer level (<4%) glucose enrichment (n = 4–8). (E) Isotopomers of glucose formed by [U-13C]lactate/pyruvate during liver perfusion and reported in the 13C NMR spectrum of glucose C2 were not altered by the addition of propionate (n = 3). Glucose isotopomers in carbons 1–3 (black circles are 13C) that contribute to the NMR signal are indicated above the corresponding signal. (F) Modeling the effect of incomplete OAA/fumarate equilibration in the TCA cycle predicted that [U-13C]lactate/pyruvate (white circles) would underestimate pyruvate cycling (PK+ME) and overestimate GNG more severely than [U-13C]propionate (gray circles). The highlighted area around 80% to 85% is the experimentally expected degree of randomization (3, 19). (G) Relative fluxes reported by [U-13C]lactate/pyruvate underestimated pyruvate cycling and overestimated GNG relative to [U-13C]propionate when simple equations (64) were used (left panel), but gave identical values when randomization was fit using a regression model (right panel) (n = 3–4). Data are shown as mean ± SEM. Statistical differences were detected by 2-tailed t test. *P < 0.05; **P < 0.001.