The Clock‐NAD+‐Sirtuin connection in nonalcoholic fatty liver disease
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 i...
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Published in | Journal of cellular physiology Vol. 237; no. 8; pp. 3164 - 3180 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
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01.08.2022
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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.
Graphical
Central clock machinery maintains the liver homeostasis via the metabolic regulators Nicotinamide adenine dinucleotide (NAD+) and sirtuins. |
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AbstractList | 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. 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. Graphical Central clock machinery maintains the liver homeostasis via the metabolic regulators Nicotinamide adenine dinucleotide (NAD+) and sirtuins. 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. |
Author | Nagarajan, Perumal Ramakrishna, Gayatri Aggarwal, Savera Trehanpati, Nirupma |
Author_xml | – sequence: 1 givenname: Savera surname: Aggarwal fullname: Aggarwal, Savera organization: Institute of Liver and Biliary Sciences – sequence: 2 givenname: Nirupma surname: Trehanpati fullname: Trehanpati, Nirupma organization: Institute of Liver and Biliary Sciences – sequence: 3 givenname: Perumal surname: Nagarajan fullname: Nagarajan, Perumal organization: National Institute of Immunology – sequence: 4 givenname: Gayatri orcidid: 0000-0003-4345-294X surname: Ramakrishna fullname: Ramakrishna, Gayatri email: rgayatri@ilbs.in organization: Institute of Liver and Biliary Sciences |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/35616339$$D View this record in MEDLINE/PubMed |
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Keywords | NAD Clock genes (CLOCK and BMAL1) NAFLD/MAFLD Sirtuin circadian rhythm |
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Snippet | Nonalcoholic or metabolic associated fatty liver disease (NAFLD/MAFLD) is a hepatic reflection of metabolic derangements characterized by excess fat deposition... Abstract Nonalcoholic or metabolic associated fatty liver disease (NAFLD/MAFLD) is a hepatic reflection of metabolic derangements characterized by excess fat... |
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SubjectTerms | Acetylation Adenine Biological clocks Biosynthesis BMAL1 protein Circadian rhythm Circadian rhythms Circuits Clock genes (CLOCK and BMAL1) Control theory Deacetylation Fatty liver Feedback loops Gene expression Genes Hepatocytes Homeostasis Lipid metabolism Lipids Liver Liver diseases Metabolism Metabolites NAD NAFLD/MAFLD Nicotinamide Nicotinamide adenine dinucleotide Oscillations Phenotypes Proteins SIRT1 protein Sirtuin Sirtuins |
Title | The Clock‐NAD+‐Sirtuin connection in nonalcoholic fatty liver disease |
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