Nicotinamide N-methyltransferase (NNMT) upregulation contributes to palmitate-elicited PPARγ transactivation in hepatocytes

Peroxisome Proliferator-activated Receptor γ (PPARγ) plays a pivotal role in regulating lipid metabolism and hepatic PPARg transactivation contributes to fatty liver development. Fatty acids (FAs) are well-known endogenous ligands for PPARg. Palmitate, a 16-C saturated FA (SFA) and the most abundant SFA in human circulation, is a strong inducer of hepatic lipotoxicity, a central pathogenic factor for various fatty liver diseases. In this study, using both AML12 and primary mouse hepatocytes, we investigated the effects of palmitate on hepatic PPARg transactivation and underlying mechanisms, as well as the role of PPARg transactivation in palmitate-induced hepatic lipotoxicity, all of which remain ambiguous currently. Our data revealed that palmitate exposure was concomitant with both PPARg transactivation and upregulation of nicotinamide N-methyltransferase (NNMT), a methyltransferase catalyzing the degradation of nicotinamide, the predominant precursor for cellular NAD⁺ biosynthesis. Importantly, we discovered that PPARg transactivation by palmitate was blunted by NNMT inhibition, suggesting that NNMT upregulation plays a mechanistic role in PPARg transactivation. Further investigations uncovered that palmitate exposure is associated with intracellular NAD⁺ decline and NAD⁺ replenishment with NAD⁺-enhancing agents, nicotinamide and nicotinamide riboside, obstructed palmitate-induced PPARg transactivation, implying that cellular NAD⁺ decline resulted from NNMT upregulation represents a potential mechanism behind palmitate-elicited PPARg transactivation. At last, our data showed that the PPARg transactivation marginally ameliorated palmitate-induced intracellular triacylglycerol accumulation and cell death. Collectively, our data provided the first-line evidence supporting that NNMT upregulation plays a mechanistic role in palmitate-elicited PPARg transactivation, potentially through reducing cellular NAD⁺ contents.

NAD; NNMT; PPARgamma; lipotoxicity; palmitate.