NAMPT overexpression alleviates alcohol-induced hepatic steatosis in mice

Abstract

Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in mammalian nicotinamide adenine dinucleotide (NAD) + biosynthesis. Through its NAD + -biosynthetic activity, NAMPT influences the activity of NAD + -dependent enzymes, such as sirtuins. NAMPT is able to modulate processes involved in the pathogenesis of non-alcohol induced fatty liver disease (NAFLD), but the roles NAMPT plays in development of alcoholic liver disease (ALD) still remain unknown. Here, we show that ethanol treatment suppresses the expression of Nampt in hepatocytes. Consistently, chronic ethanol administration also reduces Nampt expression in the mouse liver. We next demonstrate that hepatocytes infected with Ad-NAMPT adenovirus exhibit significantly elevated intracellular NAD + levels and decreased ethanol-induced triglyceride (TG) accumulation. Similarly, adenovirus-mediated overexpression of NAMPT in mice ameliorates ethanol induced hepatic steatosis. Moreover, we demonstrate that SIRT1 is required to mediate the effects of NAMPT on reduction of hepatic TG accumulation and serum ALT, AST levels in ethanol-fed mice. Our results provide important insights in targeting NAMPT for treating alcoholic fatty liver disease.

NAD+/sirtuin metabolism is enhanced in response to cold‐induced changes in lipid metabolism in mouse liver

“…So far, metabolic adaptive changes occur in the liver under cold exposure, but it is unknown how these changes are regulated. Emerging evidences suggest that the NAD + /SIRT system plays essential roles in hepatic metabolic health [40–42]. Notably, Crisol et al .…”

Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights Into Cardiovascular Disease

“…Furthermore, previous murine studies have shown that ethanol administration diminished NAMPT levels, whereas overexpression of NAMPT was found to protect against steatosis. 48 Conversely, the associations between well-described proteins and poorly understood genes can further elucidate biology. Levels of 2 proteins, plasminogen and angiostatin (itself a fragment of plasminogen), were linked to a variant upstream of GALNT7 (Figure S4B).…”

NAMPT-mediated NAD+ biosynthesis suppresses activation of hepatic stellate cells and protects against CCl4-induced liver fibrosis in mice

“…19,20 Notably, our previous study has demonstrated hepatic overexpression of NAMPT can alleviate alcohol-induced liver steatosis and inflammation. 21 Intriguingly, accumulating evidence has shown that boosting NAD + levels by supplementing NAD + intermediates, such as NAM, NMN, and NR, can ameliorate age-associated pathological abnormalities and fatty liver disease. [26][27][28] Mitchell et al have revealed that supplementing NAM protects the liver function, glucose metabolism, and overall health of aging mice.…”

“…17,18 Moreover, accumulating evidence has shown that NAMPT plays a critical role in modulating the development of diet-and alcohol-induced hepatic steatosis. [19][20][21] Interestingly, a recent study has demonstrated lower NAMPT protein abundance in CCl 4 -induced fibrotic mouse liver samples, indicating NAMPT might be an important regulator for progression of liver fibrosis. 22 However, the effects of NAMPT on the pathogenesis of liver fibrosis, especially on HSC activation are largely unknown.…”