The Clock‐NAD⁺‐Sirtuin connection in nonalcoholic fatty liver disease

Abstract

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.

Steatotic liver disease induced by TCPOBOP-activated hepatic constitutive androstane receptor: Primary and secondary gene responses with links to disease progression

“…One gene, DUSP1, is a major negative regulator of MAP kinase signaling that is decreased in MASLD patients and shows increased expression following gastrectomy linked to the amelioration of liver disease [94]. The second gene, SIRT1, protects cells from metabolic stress and steatotic liver disease by deacetylating proteins associated with lipid metabolism [95, 96]. A third inhibited late upstream regulator, CITED2, is a transcriptional co-activator that promotes hepatic gluconeogenesis [97].…”

“…Upstream regulators specifically activated at the 2 wk TCPOBOP time point included: STAT1, which promotes MASH [88,89]; MYD88, which induces liver inflammation and M2 macrophage polarization [90,91]; and several NFKB inflammatory pathway regulators [93]. Late upstream regulators, including the MASLD protective factors DUSP1 [94] and SIRT1 [95,96], were predicted to be inhibited by TCPOBOP exposure, and may thus contribute to steatotic liver disease progression. Macrophage activation and reactive oxygen species production and metabolism, and to a lesser extent inflammation, were identified as Disease and Bio Functions strongly enriched after 2 wk but not after 1 d TCPOBOP exposure.…”

“…Upstream regulators specifically activated at the 2 wk TCPOBOP time point included: STAT1, which promotes MASH [88, 89]; MYD88, which induces liver inflammation and M2 macrophage polarization [90, 91]; and several NFKB inflammatory pathway regulators [93]. Late upstream regulators, including the MASLD protective factors DUSP1 [94] and SIRT1 [95, 96], were predicted to be inhibited by TCPOBOP exposure, and may thus contribute to steatotic liver disease progression.…”

Association between type 2 diabetes mellitus and body composition based on MRI fat fraction mapping

“…Hepatic fat deposition is characterized by the accumulation of TG within hepatocytes ( 42 ). Previous studies have shown an association between hepatic fat deposition and T2DM.…”

Berberine Ameliorates Metabolic-Associated Fatty Liver Disease Mediated Metabolism Disorder and Redox Homeostasis by Upregulating Clock Genes: Clock and Bmal1 Expressions

“…Especially, when the circadian Clock component Bmal1 is disrupted, the subsequent endocrine adaptation has an important impact on insulin sensitivity, liver disease, and the metabolic syndrome [ 11 , 12 ]. The rhythmic expression of Bmal1 and Clock as master Clock-controlled genes are significantly involved in lipid metabolism and fatty liver disorder [ 13 ].…”