(P16-035-23) Nicotinamide N-Methyltransferase (NNMT) Upregulation Contributes to Palmitate-Elicited PPARγ Transactivation in Hepatocytes

Objectives: Peroxisome proliferator-activated receptor γ (PPARγ) plays a pivotal role in regulating lipid metabolism and hepatic PPARg transactivation contributes to fatty liver development. Although it has been well-documented that PPARg is activated in response to a variety of long-chain fatty acids, few studies were conducted to examine whether and how palmitate, the most abundant SFA in human circulation and a principal lipotoxicity- inducer, affects PPARg transactivation in hepatocytes. Nicotinamide N-methyltransferase (NNMT) is a methyltransferase that catalyzes S-adenosylmethionine (SAM)-dependent methylation and subsequent degradation of nicotinamide, a predominant precursor for cellular NAD+ regeneration via the salvage pathway and emerging to play a critical role in regulating metabolism and energy homeostasis. In this study, we investigated the effects of palmitate on hepatic PPARg transactivation and underlying mechanisms.

Methods: Fatty acid (palmitate and oleate) exposure of hepatocytes (AML12 and primary mouse hepatocytes) was employed as our in vitro experiment model to examine the effects of different types of fatty acids on hepatic PPARg transactivation, NNMT expression, as well as whether and how NNMT upregulation contributes to palmitate-triggered PPARg transactivation.

Results: Palmitate exposure was concomitant with both PPARg transactivation and upregulation of NNMT. PPARg transactivation by palmitate was blunted by NNMT inhibition, suggesting that NNMT upregulation plays a mechanistic role in PPARg transactivation. Palmitate exposure is associated with intracellular NAD+ decline and NAD+ replenishment with NAD+-enhancing agents obstructed palmitate-induced PPARg transactivation, implying that cellular NAD+ decline resulted from NNMT upregulation represents a potential mechanism behind palmitate-elicited PPARg transactivation.

Conclusions: 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.

Funding Sources: US NIH Grants NIAAA R01AA026603 (ZS), NIAAA R01AA030255 (ZS), and NIDDK R01DK131038 (JCC).