Ethanol-induced fat accumulation, the earliest and most common response of the liver to ethanol exposure, may be involved in the pathogenesis of liver diseases. Isoliquiritigenin (ISL), an important constituent of Glycyrrhizae Radix, is a chalcone derivative that exhibits antioxidant, anti-inflammatory, and phytoestrogenic activities. However, the effect of ISL treatment on lipid accumulation in hepatocytes and alcoholic hepatitis remains unclear. Therefore, we evaluated the effect and underlying mechanism of ISL on ethanol-induced hepatic steatosis by treating AML-12 cells with 200 mM ethanol and/or ISL (0~50 μM) for 72 hr. Lipid accumulation was assayed by oil red O staining, and the expression of sirtuin1 (SIRT1), sterol regulatory element-binding protein-1c (SREBP-1c), AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor alpha (PPARα) was studied by western blotting. Our results indicated that ISL treatment upregulated SIRT1 expression and downregulated SREBP-1c expression in ethanol-treated cells. Similarly, oil red O staining revealed a decrease in ethanol-induced fat accumulation upon co-treatment of ethanol-treated cells with 10, 20, and 50 μM of ISL. These findings suggest that ISL can reduce ethanol induced-hepatic lipogenesis by activating the SIRT1-AMPK pathway and thus improve lipid metabolism in alcoholic fatty livers.
Prostate cancer (PCa) is the most commonly diagnosed genital cancer in men worldwide. Around 80% of the patients who developed advanced PCa suffered from bone metastasis, with a sharp drop in the survival rate. Despite great efforts, the detailed mechanisms underlying castration-resistant PCa (CRPC) remain unclear. Sirtuin 5 (SIRT5), an NAD+-dependent desuccinylase, is hypothesized to be a key regulator of various cancers. However, compared to other SIRTs, the role of SIRT5 in cancer has not been extensively studied. Here, we revealed significantly decreased SIRT5 levels in aggressive PCa cells relative to the PCa stages. The correlation between the decrease in the SIRT5 level and the patient’s reduced survival rate was also confirmed. Using quantitative global succinylome analysis, we characterized a significant increase in the succinylation at lysine 118 (K118su) of lactate dehydrogenase A (LDHA), which plays a role in increasing LDH activity. As a substrate of SIRT5, LDHA-K118su significantly increased the migration and invasion of PCa cells and LDH activity in PCa patients. This study reveals the reduction of SIRT5 protein expression and LDHA-K118su as a novel mechanism involved in PCa progression, which could serve as a new target to prevent CPRC progression for PCa treatment.
Background/Aim: Prostate cancer (PCa) is the most commonly diagnosed genital cancer in men globally. Among patients who develop advanced PCa, 80% are affected by bone metastasis, with a sharp drop in survival rate. Despite efforts, the details of mechanisms of metastasis of PCa remain unclear. SIRT5, an NAD + -dependent deacylase, is hypothesized to be a crucial regulator of various cancers. The role of SIRT5 in cancer has not been extensively studied compared to other SIRTs. In this study, we showed significantly decreased levels of SIRT5 in PC-3M, a highly aggressive PC-3 cell variant. Materials and Methods: We characterized the differentially expressed proteins between parental and SIRT5 KO PC-3 cells using quantitative proteomics analysis. Results: A significant increase in expression of interleukin-1β (IL-1β) in SIRT5 KO cells was observed, and the PI3K/AKT/NF-ĸB signaling pathway was found significantly elevated in SIRT5 KO cells by the Gene Ontology annotation and KEGG pathway functional enrichment analysis. Moreover, we confirmed that SIRT5 can bind PI3K by immunoprecipitation analysis. Conclusion: This study is the first to demonstrate a relationship between SIRT5 and PCa metastasis, suggesting that SIRT5-mediated inhibition of the PI3K/AKT/NK-kB pathway is reduced for secondary metastasis from bone to other tissues.Silent information regulator 2-like proteins (sirtuin, SIRT) are highly conserved proteins with nicotinamide adenine dinucleotide (NAD)-dependent deacylase activity and are classified as class III histone deacetylase enzymes (1, 2). There are seven types of SIRTs (1-7) in mammals, and they are known to be present in all organelles in cells and play a characteristic role (3). SIRTs have specific functions in cancer and normal cells. Numerous studies have revealed that SIRTs play critical roles in the progression of cancer and metastases by regulating pathways of angiogenesis, inflammation, and epithelial-to-mesenchymal transition (4-6). Among the seven SIRTs, SIRT5 is characterized as a NAD + -dependent lysine deacetylase, demalonylase, desuccinylase, and deglutarylase (7). SIRT5 is also involved in cell metabolism, including glycolysis, tricarboxylic acid cycle, fatty acid oxidation, nitrogen metabolism, pentose phosphate pathway, antioxidant defense, and apoptosis (8). Particularly, SIRT5 plays a role in tumorigenesis by regulating desuccinylation involved in specific enzymatic activities (9,10). SIRT5 also has important regulatory roles in tumor progression in the liver and gastric cancer (11,12).
Calorie restriction (CR) is the most frequently studied mechanism for increasing longevity, protecting against stress, and delaying age-associated diseases. Most studies have initiated CR in young animals to determine the protective effects against aging. Although aging phenomena are well-documented, the molecular mechanisms of aging and CR remain unclear. In this study, we observe changes in hepatic proteins upon age-related and diet-restricted changes in the rat liver using quantitative proteomics. Quantitative proteomes are measured using tandem mass tag labeling followed by LC-MS/MS. We compare protein levels in livers from young (6 months old) and old (25 months old) rats with 40% calorie-restricted (YCR and OCR, respectively) or ad libitum diets. In total, 44 279 peptides and 3134 proteins are identified and 260 differentially expressed proteins are found. Functional enrichment analysis show that these proteins are mainly involved in glucose and fatty acid metabolism-related processes, consistent with the theory that energy metabolism regulation is dependent on age-related and calorie-restricted changes in liver tissue. In addition, proteins mediating inflammation and gluconeogenesis are increased in OCR livers, but not YCR livers. These results show that CR in old rats might not have antiaging benefits because liver inflammation is increased.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.