Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India.
Department of Experimental Animal Facility, National Institute of Immunology, New Delhi, India.
J Cell Physiol. 2022 Aug;237(8):3164-3180. doi: 10.1002/jcp.30772. Epub 2022 May 26.
Nonalcoholic or metabolic associated fatty liver disease (NAFLD/MAFLD) is a hepatic reflection of metabolic derangements characterized by excess fat deposition in the hepatocytes. Identifying metabolic regulatory nodes in fatty liver pathology is essential for effective drug targeting. Fatty liver is often associated with circadian rhythm disturbances accompanied with alterations in physical and feeding activities. In this regard, both sirtuins and clock machinery genes have emerged as critical metabolic regulators in maintaining liver homeostasis. Knockouts of either sirtuins or clock genes result in obesity associated with the fatty liver phenotype. Sirtuins (SIRT1-SIRT7) are a highly conserved family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases, protecting cells from metabolic stress by deacetylating vital proteins associated with lipid metabolism. Circadian rhythm is orchestrated by oscillations in expression of master regulators (BMAL1 and CLOCK), which in turn regulate rhythmic expression of clock-controlled genes involved in lipid metabolism. The circadian metabolite, NAD+ , serves as a crucial link connecting clock genes to sirtuin activity. This is because, NAMPT which is a rate limiting enzyme in NAD+ biosynthesis is transcriptionally regulated by the clock genes and NAD+ in turn is a cofactor regulating the deacetylation activity of sirtuins. Intriguingly, on one hand the core circadian clock regulates the sirtuin activity and on the other hand the activated sirtuins regulate the acetylation status of clock proteins thereby affecting their transcriptional functions. Thus, the Clock-NAD+-Sirtuin connection represents a novel "feedback loop" circuit that regulates the metabolic machinery. The current review underpins the importance of NAD+ on the sirtuin and clock connection in preventing fatty liver disorder.
非酒精性或代谢相关脂肪性肝病（NAFLD/MAFLD）是一种代谢紊乱的肝脏表现，其特征是肝细胞内脂肪沉积过多。鉴定脂肪性肝病病理学中的代谢调节节点对于有效的药物靶向至关重要。脂肪性肝病通常与昼夜节律紊乱有关，伴随着身体活动和进食活动的改变。在这方面，Sirtuins 和时钟机制基因已成为维持肝脏内稳态的关键代谢调节剂。Sirtuins 或时钟基因的敲除会导致肥胖，并伴有脂肪肝病表型。Sirtuins（SIRT1-SIRT7）是一种高度保守的烟酰胺腺嘌呤二核苷酸（NAD+）依赖性去乙酰化酶家族，通过去乙酰化与脂质代谢相关的重要蛋白质来保护细胞免受代谢应激。昼夜节律由主调控因子（BMAL1 和 CLOCK）的表达波动来协调，而主调控因子又调节参与脂质代谢的时钟控制基因的节律性表达。昼夜节律代谢物 NAD+是连接时钟基因和 Sirtuin 活性的关键环节。这是因为，NAD+生物合成的限速酶 NAMPT 受时钟基因的转录调控，而 NAD+反过来又是调节 Sirtuin 去乙酰化活性的辅助因子。有趣的是，一方面核心生物钟调节 Sirtuin 活性，另一方面激活的 Sirtuin 调节时钟蛋白的乙酰化状态，从而影响它们的转录功能。因此，Clock-NAD+-Sirtuin 连接代表了一种调节代谢机制的新型“反馈环”电路。本综述强调了 NAD+在 Sirtuin 和时钟连接中防止脂肪性肝病紊乱的重要性。
