The role of odd chain fatty acids on hepatocyte and monocyte function

Abstract

Lipid-induced dysfunction of the liver is becoming increasingly prevalent and may be an essential link between obesity and type 2 diabetes (T2DM). Elevated circulating saturated fatty acids (FA) like palmitate have been shown to contribute to hepatic insulin resistance and chronic low-grade inflammation leading to T2DM while other plasma unsaturated FA appear protective. Strong emerging evidence point to the potentially protective effect of odd chain FA (OCSFA) on T2DM disease development; however, no study has looked at the cellular mechanisms underpinning its effect. The transcription factor PPAR alpha is involved in regulating hepatic lipid accumulation by upregulating genes responsible for FA transport and has been shown to alter hepatic insulin sensitivity, as well as an anti-inflammatory effect on monocytes. Therefore, the hypothesis that OCSFA predict fasting plasma glucose and their role in modulating hepatocyte and monocyte function (by activating PPAR alpha) has been examined. Analysis of the FA profile of a healthy and T2DM cohort showed that C15:0 occurred in higher proportions in healthy controls compared to T2DM (median difference 0.07%, p = 0.05) and was found to be negatively correlated with fasting blood glucose (p = 0.002). In a model of terminally differentiated HepG2 cells, the data showed that C15:0 ameliorated palmitate-induced dysfunction of glucose output (p < 0.001) and glycogen production (p < 0.001); and increased PPAR alpha transcriptional activity by 20% (p < 0.01). Furthermore, there was a 72% reduction in TNFα production in monocytes pre-exposed to C15:0 before LPS stimulation compared to controls (p < 0.01). Taken together, the potentially protective effect of C15:0 regarding T2DM development may be due to PPAR alpha-related attenuation of chronic inflammation and improvement of hepatocyte metabolism.