The Beneficial Roles of SIRT1 in Neuroinflammation-Related Diseases
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ABSTRACT:
SUBMITTER: Jiao F
PROVIDER: S-EPMC7519200 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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Project description:Drug-induced liver injury (DILI) is a major cause of acute liver failure (ALF) as a result of accumulated drugs in the human body metabolized into toxic agents and helps generate heavy oxidative stress, inflammation, and apoptosis, which induces necrosis in hepatocytes and ultimately damages the liver. Sirtuin 1 (SIRT1) is said to have multiple vital roles in cell proliferation, aging, and antistress systems of the human body. The levels of SIRT1 and its activation precisely modulate its critical role in the interaction between multiple step procedures of DILI. The nuclear factor kappa-light-chain-enhancer of activated B cell- (NF-κB-) mediated inflammation signaling pathway, reactive oxygen species (ROS), DNA damage, mitochondrial membrane potential collapse, and endoplasmic reticulum (ER) stress also contribute to aggravate DILI. Apoptosis is regarded as the terminal reaction followed by multiple signaling cascades including caspases, p53, and mitochondrial dysfunction which have been said to contribute in DILI. The SIRT1 activator is regarded as a potential candidate for DILI, because the former could inhibit signaling of p53, NF-κB, and ER stress. On the other hand, overexpression of SIRT1 also enhances the activation of antioxidant responses via Kelch-like ECH-associated protein 1- (Keap1-) nuclear factor- (erythroid-derived 2-) like 2 (Nrf2) signaling. The current manuscript will highlight the mechanism of DILI and the interaction of SIRT1 with various cytoplasmic factors leading to DILI along with the summary of potent SIRT1 agonists.
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Project description:Fatty liver diseases, which are commonly associated with high-fat/calorie diet, heavy alcohol consumption and/or other metabolic disorder causes, lead to serious medical concerns worldwide in recent years. It has been demonstrated that metabolic homeostasis disruption is most likely to be responsible for this global epidemic. Sirtuins are a group of conserved nicotinamide adenine dinucleotide (NAD+) dependent histone and/or protein deacetylases belonging to the silent information regulator 2 (Sir2) family. Among seven mammalian sirtuins, sirtuin 1 (SIRT 1) is the most extensively studied one and is involved in both alcoholic and nonalcoholic fatty liver diseases. SIRT1 plays beneficial roles in regulating hepatic lipid metabolism, controlling hepatic oxidative stress and mediating hepatic inflammation through deacetylating some transcriptional regulators against the progression of fatty liver diseases. Here we summarize the latest advances of the biological roles of SIRT1 in regulating lipid metabolism, oxidative stress and inflammation in the liver, and discuss the potential of SIRT1 as a therapeutic target for treating alcoholic and nonalcoholic fatty liver diseases.
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Project description:The purpose of this study is to investigate the role of SIRT1 in high-fat diet-induced liver steatosis and insulin resistance. SIRT1 is a nuclear enzyme that could remove an acetyl-group from target proteins by using NAD as co-substrate. Homologs of this protein in yeast and the roundworm C. elegans are able to delay the aging process in response to nutrients. However, the molecular mechanism by which SIRT1 sense the environment to mediate this response are poorly understood. We have shown that when chronically fed with a 40%-fat diet, SIRT1 heterozygous animals gain significantly more weight compared to wild type littermates. They are also hyperinsulimia, more insulin-resistant, and accumulate more lipids in liver. Interestingly, these animals also show signs of premature aging, such as an early appearance of gray fur, defective motor activity, and decreased fertility. In this microarray study, we analyzed the gene expression profiles in the liver of WT low-fat diet, Het low-fat diet, WT high-fat diet, and Het high-fat diet using Agilent Whole Genome Mouse 4x44 multiplex format oligo arrays following the Agilent-1-color microarray-based gene expression analysis protocol. This microarray analysis concluded that SIRT1 Het mice reponsed to the high-fat diet differently from the WT control mice. Liver total RNAs from SIRT1 WT and Het mice that were fed with either a low-fat diet or a high-fat diet for 34 weeks were used for a microarray gene expression study. Three biological replicates for each group were used.
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Project description:The purpose of this study is to investigate the role of SIRT1 in high-fat diet-induced liver steatosis and insulin resistance. SIRT1 is a nuclear enzyme that could remove an acetyl-group from target proteins by using NAD as co-substrate. Homologs of this protein in yeast and the roundworm C. elegans are able to delay the aging process in response to nutrients. However, the molecular mechanism by which SIRT1 sense the environment to mediate this response are poorly understood. We have shown that when chronically fed with a 40%-fat diet, SIRT1 heterozygous animals gain significantly more weight compared to wild type littermates. They are also hyperinsulimia, more insulin-resistant, and accumulate more lipids in liver. Interestingly, these animals also show signs of premature aging, such as an early appearance of gray fur, defective motor activity, and decreased fertility. In this microarray study, we analyzed the gene expression profiles in the liver of WT low-fat diet, Het low-fat diet, WT high-fat diet, and Het high-fat diet using Agilent Whole Genome Mouse 4x44 multiplex format oligo arrays following the Agilent-1-color microarray-based gene expression analysis protocol. This microarray analysis concluded that SIRT1 Het mice reponsed to the high-fat diet differently from the WT control mice.
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