Direct inhibitory effects of phospholipase A2 enzymatic product lysophosphatidylcholine (LPC) on hepatic mitochondria

Suppression of the pancreatic group 1b phospholipase A2 (PLA2) protects against diet‐induced obesity, diabetes, and dyslipidemia. PLA2‐deficient mice have increased postprandial hepatic fatty acid oxidation (FAO) compared to wild type, a difference that is abolished with addition of LPC. We hypothesize that LPC directly inhibits FAO in hepatic mitochondria thereby contributing to of the pathogenesis of obesity, diabetes and dyslipidemia. Thus, we examined the effects of LPC on respiratory function of isolated liver mitochondria with fatty acids and Krebs cycle substrates. LPC inhibited rate of state 3 (+ADP) and partially stimulated rate of state 4 (−ADP) respiration with fatty acid and Krebs cycle substrates. The coupling of ADP to ATP was also inhibited by LPC. These inhibitory effects of LPC on oxidative phosphorylation of mitochondria were neither due to membrane damage nor inhibition of electron transport chain. We conclude that inhibition of FAO in mitochondria and their dysfunction may contribute to intracellular and plasma lipid accumulation and dyslipidemia, obesity, and diabetes. (Works Supported by NIH grant #R01 DK069967).