Hepatic NAD⁺ deficiency as a therapeutic target for non‐alcoholic fatty liver disease in ageing

Abstract

Hepatic concentrations of NAD + , protein levels of nicotinamide phosphoribosyltransferase (NAMPT) and several other critical enzymes regulating NAD + biosynthesis, were compared in middle-aged and aged mice or patients. The influences of NAD + decline on the steatosis and steatohepatitis were evaluated in wild-type and H247A dominant-negative, enzymically-inactive NAMPT transgenic mice (DN-NAMPT) given normal or high-fat diet (HFD). KEY RESULTSHepatic NAD + level decreased in aged mice and humans. NAMPT-controlled NAD + salvage, but not de novo biosynthesis pathway, was compromised in liver of elderly mice and humans. Given normal chow, middle-age DN-NAMPT mice displayed systemic NAD + reduction and had moderate NAFLD phenotypes, including lipid accumulation, enhanced oxidative stress, triggered inflammation and impaired insulin sensitivity in liver. All these NAFLD phenotypes, especially release of pro-inflammatory factors, Kupffer cell accumulation, monocytes infiltration, NLRP3 inflammasome pathway and hepatic fibrosis (Masson's staining and α-SMA staining), deteriorated further under HFD challenge. Oral administration of nicotinamide riboside, a natural NAD + precursor, completely corrected these NAFLD phenotypes induced by NAD + deficiency alone or HFD, whereas adenovirus-mediated SIRT1 overexpression only partially rescued these phenotypes. CONCLUSIONS AND IMPLICATIONSThese results provide the first evidence that ageing-associated NAD + deficiency is a critical risk factor for NAFLD, and suggest that supplementation with NAD + substrates may be a promising therapeutic strategy to prevent and treat NAFLD.

Silybin inhibits NLRP3 inflammasome assembly through the NAD+/SIRT2 pathway in mice with nonalcoholic fatty liver disease

“…Our results confirmed that the ER and mitochondria were close to each other around the nucleus, and their motion was dependent on acetylated α‐tubulin and NAD+ levels in the HFD‐fed mice model. Reduction of hepatic NAD + was closely related to lipid accumulation, enhanced oxidative stress, inflammation, and impaired insulin sensitivity in the liver (11, 34). NAD + deficiency is a critical risk factor for NAFLD.…”

The role of caloric load and mitochondrial homeostasis in the regulation of the NLRP3 inflammasome

“…Furthermore, in the same study, the in vitro supplementation with the NAD + -salvage metabolite NR blunted refeeding activation effect on the NLRP3 inflammasome. Interestingly, other groups have found a similar inhibitory effect of NAD + repletion by NR supplementation on hepatosteatosis, hepatic inflammation and NLRP3 inflammasome activation in mice [76, 116, 117]. Whether NR could function to suppress the NLRP3 inflammasome has the potential to be explored as a therapeutic agent, given its myriad of other beneficial effects in vivo [118–121].…”

“…Emerging evidence supports that these proteins, and also their cofactor NAD + , are involved in metabolic diseases associated with inflammation [75, 76]. …”

NAD replenishment with nicotinamide mononucleotide protects blood–brain barrier integrity and attenuates delayed tissue plasminogen activator‐induced haemorrhagic transformation after cerebral ischaemia

“…The effects of NAD on a group of NAD-dependent proteins, such as the sirtuin family of proteins and PARP1, are the main mechanisms behind NAD's biological functions (Garten et al, 2015;Zhang et al, 2016;Jokinen et al, 2017). Depletion of intracellular NAD is a common pathway in many pathophysiological events, including ageing, metabolic disorders and cerebral ischaemia (Yang et al, 2002;Massudi et al, 2012;Zhang et al, 2016;Zhou et al, 2016;Wang et al, 2016a). The administration of nicotinamide mononucleotide (NMN) or nicotinamide riboside, two NAD precursors, as a supplement is able to enhance NAD levels and is used to treat high-fat-induced obesity/fatty liver (Yoshino et al, 2011;Uddin et al, 2016;Zhou et al, 2016).…”

“…Depletion of intracellular NAD is a common pathway in many pathophysiological events, including ageing, metabolic disorders and cerebral ischaemia (Yang et al, 2002;Massudi et al, 2012;Zhang et al, 2016;Zhou et al, 2016;Wang et al, 2016a). The administration of nicotinamide mononucleotide (NMN) or nicotinamide riboside, two NAD precursors, as a supplement is able to enhance NAD levels and is used to treat high-fat-induced obesity/fatty liver (Yoshino et al, 2011;Uddin et al, 2016;Zhou et al, 2016). We and other groups have demonstrated that NMN protects against post-ischaemic NAD degradation and decreases brain damage after cerebral ischaemia Zhao et al, 2014;Park et al, 2016).…”