OXPHOS-Mediated Induction of NAD+ Promotes Complete Oxidation of Fatty Acids and Interdicts Non-Alcoholic Fatty Liver Disease.
OXPHOS is believed to play an important role in non-alcoholic fatty liver disease (NAFLD), however, precise mechanisms whereby OXPHOS influences lipid homeostasis are incompletely understood. We previously reported that ectopic expression of LRPPRC, a protein that increases cristae density and OXPHOS, promoted fatty acid oxidation in cultured primary hepatocytes. To determine the biological significance of that observation and define underlying mechanisms, we have ectopically expressed LRPPRC in mouse liver in the setting of NAFLD. Interestingly, ectopic expression of LRPPRC in mouse liver completely interdicted NAFLD, including inflammation. Consistent with mitigation of NAFLD, two markers of hepatic insulin resistance--ROS and PKCε activity--were both modestly reduced. As reported by others, improvement of NAFLD was associated with improved whole-body insulin sensitivity. Regarding hepatic lipid homeostasis, the ratio of NAD+ to NADH was dramatically increased in mouse liver replete with LRPPRC. Pharmacological activators and inhibitors of the cellular respiration respectively increased and decreased the [NAD+]/[NADH] ratio, indicating respiration-mediated control of the [NAD+]/[NADH] ratio. Supporting a prominent role for NAD+, increasing the concentration of NAD+ stimulated complete oxidation of fatty acids. Importantly, NAD+ rescued impaired fatty acid oxidation in hepatocytes deficient for either OXPHOS or SIRT3. These data are consistent with a model whereby augmented hepatic OXPHOS increases NAD+, which in turn promotes complete oxidation of fatty acids and protects against NAFLD.
Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, United States of America.
Thomas E
TE
Akie
Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, United States of America.
Lijun
L
Liu
Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, United States of America.
Minwoo
M
Nam
Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, United States of America.
Shi
S
Lei
Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, United States of America.
Marcus P
MP
Cooper
D000818:Animals; D059305:Diet, High-Fat; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009243:NAD / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D061251:Primary Cell Culture; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D056566:Sirtuin 3 / Q000172:deficiency / Q000235:genetics
D005227:Fatty Acids; C486222:Lrpprc protein, mouse; D009363:Neoplasm Proteins; C525046:Sirt3 protein, mouse; D009243:NAD; C497256:Prkce protein, mouse; D051744:Protein Kinase C-epsilon; D056566:Sirtuin 3