OXPHOS-Mediated Induction of NAD+ Promotes Complete Oxidation of Fatty Acids and Interdicts Non-Alcoholic Fatty Liver Disease

Abstract

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.

Lipidomics unveils lipid dyshomeostasis and low circulating plasmalogens as biomarkers in a monogenic mitochondrial disorder

“…This suggests lower NAD + bioavailability, which would be unfavorable for the 3-hydroxyacyl-CoA-dehydrogenase activity. The importance of the liver in eliciting the observed plasma metabolite changes, including hydroxylated ACs, is supported by our findings in H-Lrpprc -/mice, and previous studies documenting impaired LCFA oxidation in liver mitochondria (14)(15)(16). Conversely, overexpression of Lrpprc in mouse liver improved LCFA oxidation and was accompanied by increased hepatic OXPHOS and tissue NAD + levels (16).…”

“…Lipidomics and molecular analyses in the H-Lrpprc -/mouse corroborate the plasma lipid dyshomeostasis of LSFC patients, including lower plasmalogens, and unveil a role of the liver. The H-Lrpprc -/mouse model, which harbors a liver-specific loss of function of Lrpprc, was previously investigated and shown to display at 5 weeks major mitochondrial bioenergetic defects in the liver, which are characteristic of LSFC patients (>90% and 80% lower protein levels for LRPPRC and COX subunit COX1, respectively), and to recapitulate histopathological changes characteristic of microvesicular steatohepatitis (15,16). In the present study, we used H-Lrpprc -/mice that had reached 14 weeks of age, and confirmed lower protein levels in liver for LRPPRC and COX subunit MTCO1 (60% and 30%, respectively; Supplemental Figure 3), although the observed changes were less pronounced than at 5 weeks.…”

“…These patients are also affected by hepatic microvesicular steatosis (8,(13)(14)(15). Hepatic steatosis has also been reported in mice harboring liver-specific inactivation of Lrpprc (H-Lrpprc -/-) (15) and is rescued by overexpression of Lrpprc in mouse liver (13,14,16). Of broader relevance, mitochondrial dysfunction is considered an important actor in hepatic steatosis, as it occurs in nonalcoholic fatty liver disease (NAFLD) and also more common chronic diseases (17).…”

Systems approach to characterize the metabolism of liver cancer stem cells expressing CD133

“…2b and Supplementary Table S3). Fatty acid oxidation requires NAD + , which induces fatty acid oxidation to generate ATP40. Moreover, NAD + can activate the upstream signaling pathway of fatty acid oxidation by activation of SIRT1, a NAD + -dependent protein deacetylase (Fig.…”

Mitochondria–Power Players in Kidney Function?

“…However, the studies of Tran et al did not examine whether restoration of cellular NAD ultimately preserved mitochondrial NAD concentrations, mitochondrial oxidative phosphorylation, or ATP production. Further, it is also possible that other beneficial effects of PGC1/ such as mitochondrial biogenesis can act in other contexts to preserve mitochondrial oxidative phosphorylation leading to restoration of NAD concentrations [5].…”