RÉSUMÉ
Glaucoma is characterized by the progressive degeneration of retinal ganglion cells (RGCs) and their axons, and its risk increases with aging. Yet comprehensive insights into the complex mechanisms are largely unknown. Here, we found that anti-aging molecule Sirt6 was highly expressed in RGCs. Deleting Sirt6 globally or specifically in RGCs led to progressive RGC loss and optic nerve degeneration during aging, despite normal intraocular pressure (IOP), resembling a phenotype of normal-tension glaucoma. These detrimental effects were potentially mediated by accelerated RGC senescence through Caveolin-1 upregulation and by the induction of mitochondrial dysfunction. In mouse models of high-tension glaucoma, Sirt6 level was decreased after IOP elevation. Genetic overexpression of Sirt6 globally or specifically in RGCs significantly attenuated high tension-induced degeneration of RGCs and their axons, whereas partial or RGC-specific Sirt6 deletion accelerated RGC loss. Importantly, therapeutically targeting Sirt6 with pharmacological activator or AAV2-mediated gene delivery ameliorated high IOP-induced RGC degeneration. Together, our studies reveal a critical role of Sirt6 in preventing RGC and optic nerve degeneration during aging and glaucoma, setting the stage for further exploration of Sirt6 activation as a potential therapy for glaucoma.
Sujet(s)
Vieillissement , Modèles animaux de maladie humaine , Glaucome , Nerf optique , Cellules ganglionnaires rétiniennes , Sirtuines , Animaux , Cellules ganglionnaires rétiniennes/métabolisme , Cellules ganglionnaires rétiniennes/anatomopathologie , Souris , Sirtuines/métabolisme , Sirtuines/génétique , Glaucome/métabolisme , Glaucome/génétique , Glaucome/anatomopathologie , Glaucome/étiologie , Nerf optique/métabolisme , Nerf optique/anatomopathologie , Vieillissement/métabolisme , Vieillissement/génétique , Pression intraoculaire , Humains , Axones/métabolisme , Axones/anatomopathologie , Souris knockout , Dégénérescence nerveuse/métabolismeRÉSUMÉ
Alcohol-related liver disease (ALD), a condition caused by alcohol overconsumption, occurs in three stages of liver injury including steatosis, hepatitis, and cirrhosis. DEP domain-containing protein 5 (DEPDC5), a component of GAP activities towards Rags 1 (GATOR1) complex, is a repressor of amino acid-sensing branch of the mammalian target of rapamycin complex 1 (mTORC1) pathway. In the current study, we found that aberrant activation of mTORC1 was likely attributed to the reduction of DEPDC5 in the livers of ethanol-fed mice or ALD patients. To further define the in vivo role of DEPDC5 in ALD development, we generated Depdc5 hepatocyte-specific knockout mouse model (Depdc5-LKO) in which mTORC1 pathway was constitutively activated through loss of the inhibitory effect of GATOR1. Hepatic Depdc5 ablation leads to mild hepatomegaly and liver injury and protects against diet-induced liver steatosis. In contrast, ethanol-fed Depdc5-LKO mice developed severe hepatic steatosis and inflammation. Pharmacological intervention with Torin 1 suppressed mTORC1 activity and remarkably ameliorated ethanol-induced hepatic steatosis and inflammation in both control and Depdc5-LKO mice. The pathological effect of sustained mTORC1 activity in ALD may be attributed to the suppression of peroxisome proliferator activated receptor α (PPARα), the master regulator of fatty acid oxidation in hepatocytes, because fenofibrate (PPARα agonist) treatment reverses ethanol-induced liver steatosis and inflammation in Depdc5-LKO mice. These findings provide novel insights into the in vivo role of hepatic DEPDC5 in the development of ALD.
Sujet(s)
Stéatose hépatique alcoolique/métabolisme , Protéines d'activation de la GTPase/déficit , Foie/métabolisme , Récepteur PPAR alpha/métabolisme , Animaux , Cytokines/génétique , Cytokines/métabolisme , Modèles animaux de maladie humaine , Acides gras/métabolisme , Stéatose hépatique alcoolique/génétique , Stéatose hépatique alcoolique/anatomopathologie , Stéatose hépatique alcoolique/prévention et contrôle , Femelle , Protéines d'activation de la GTPase/génétique , Médiateurs de l'inflammation , Foie/effets des médicaments et des substances chimiques , Foie/ultrastructure , Mâle , Complexe-1 cible mécanistique de la rapamycine/métabolisme , Souris knockout , Naphtyridines/pharmacologie , Oxydoréduction , Stress oxydatif , Récepteur PPAR alpha/génétique , Transduction du signalRÉSUMÉ
Significance: Fatty liver disease is a major liver disorder in the modern societies. Comprehensive understanding of the pathophysiology and molecular mechanisms is essential for the prevention and treatment of the disease. Recent Advances: Remarkable progress has been made in the recent years in basic and translational research in the field of fatty liver disease. Multiple signaling pathways have been implicated in the development of fatty liver disease, including AMP-activated protein kinase, mechanistic target of rapamycin kinase, endoplasmic reticulum stress, oxidative stress, inflammation, transforming growth factor ß, and yes1-associated transcriptional regulator/transcriptional coactivator with PDZ-binding motif (YAP/TAZ). In addition, critical molecular regulations at the transcriptional and epigenetic levels have been linked to the pathogenesis of fatty liver disease. Critical Issues: Some critical issues remain to be solved so that research findings can be translated into clinical applications. Robust and reliable biomarkers are needed for diagnosis of different stages of the fatty liver disease. Effective and safe molecular targets remain to be identified and validated. Prevention strategies require solid scientific evidence and population-wide feasibility. Future Directions: As more data are generated with time, integrative approaches are needed to comprehensively understand the disease pathophysiology and mechanisms at multiple levels from population, organismal system, organ/tissue, to cell. The interactions between genes and environmental factors require deeper investigation for the purposes of prevention and personalized treatment of fatty liver disease. Antioxid. Redox Signal. 35, 689-717.
Sujet(s)
Transduction du signal , Facteurs de transcription , Stress du réticulum endoplasmique , Foie/métabolisme , Oxydoréduction , Stress oxydatif , Facteurs de transcription/métabolismeRÉSUMÉ
BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D) and obesity are epidemiologically correlated with each other but the causal inter-relationships between them remain incompletely understood. We aimed to explore the causal relationships between the 3 diseases. METHODS: Using both UK Biobank and publicly available genome-wide association study data, we performed a 2-sample bidirectional Mendelian randomization analysis to test the causal inter-relationships between NAFLD, T2D, and obesity. Transgenic mice expressing the human PNPLA3-I148M isoforms (TghPNPLA3-I148M) were used as an example to validate causal effects and explore underlying mechanisms. RESULTS: Genetically driven NAFLD significantly increased the risk of T2D and central obesity but not insulin resistance or generalized obesity, while genetically driven T2D, body mass index and WHRadjBMI causally increased NAFLD risk. The animal study focusing on PNPLA3 corroborated these causal effects: compared to the TghPNPLA3-I148I controls, the TghPNPLA3-I148M mice developed glucose intolerance and increased visceral fat, but maintained normal insulin sensitivity, reduced body weight, and decreased circulating total cholesterol. Mechanistically, the TghPNPLA3-I148M mice demonstrated decreased pancreatic insulin but increased glucagon secretion, which was associated with increased pancreatic inflammation. In addition, transcription of hepatic cholesterol biosynthesis pathway genes was significantly suppressed, while transcription of thermogenic pathway genes was activated in subcutaneous and brown adipose tissues but not in visceral fat in TghPNPLA3-I148M mice. CONCLUSIONS: Our study suggests that lifelong, genetically driven NAFLD causally promotes T2D with a late-onset type 1-like diabetic subphenotype and central obesity; while genetically driven T2D, obesity, and central obesity all causally increase the risk of NAFLD. This causal relationship revealed new insights into how nature and nurture drive these diseases, providing novel hypotheses for disease subphenotyping. LAY SUMMARY: Non-alcoholic fatty liver disease, type 2 diabetes and obesity are epidemiologically correlated with each other, but their causal relationships were incompletely understood. Herein, we identified causal relationships between these conditions, which suggest that each of these closely related diseases should be further stratified into subtypes. This is important for accurate diagnosis, prevention and treatment of these diseases.
Sujet(s)
Diabète de type 2 , Triacylglycerol lipase/génétique , Protéines membranaires/génétique , Stéatose hépatique non alcoolique , Obésité abdominale , Animaux , Causalité , Diabète de type 2/épidémiologie , Diabète de type 2/génétique , Europe/épidémiologie , Effet fondateur , Étude d'association pangénomique , Humains , Analyse de randomisation mendélienne , Souris , Souris transgéniques , Stéatose hépatique non alcoolique/épidémiologie , Stéatose hépatique non alcoolique/génétique , Obésité abdominale/épidémiologie , Obésité abdominale/génétique , Isoformes de protéinesRÉSUMÉ
Sestrin 3 (Sesn3) belongs to a small protein family that has been implicated in multiple biological processes including anti-oxidative stress, anti-aging, cell signaling, and metabolic homeostasis. However, the role of Sesn3 in hepatocellular carcinoma (HCC) remains unclear. Here we generated a Sesn3 knockout mouse model and induced HCC development by a combination of a single dose of diethylnitrosamine and chronic feeding of a choline deficient-high fat diet. After 6â¯months of the dietary treatment, Sesn3 knockout mice developed more severe HCC with higher levels of alpha-fetoprotein, arginase 1, and cytokeratin 19, but also higher metastatic rates than wild-type mice. Histological analysis revealed elevated extracellular matrix and cancer stem cell markers including Acta2, Cd44, and Cd133. Signaling analysis showed activated IL6-Stat3 and Akt pathways. Biochemical and microscopic analyses uncovered a novel inhibitory regulation of Gli2, a downstream transcription factor of the hedgehog signaling, by Sesn3. Two of the Gli2-regulated genes - Pdgfrb and Cd44 were upregulated in the Sesn3-deficient liver tissue. In conclusion, our data suggest that Sesn3 plays a critical tumor suppressor role in the liver partly through the inhibition of the hedgehog signaling.
Sujet(s)
Cancérogènes/métabolisme , Carcinome hépatocellulaire/métabolisme , Prédisposition génétique à une maladie/génétique , Protéines du choc thermique/génétique , Protéines du choc thermique/métabolisme , Protéines Hedgehog/métabolisme , Tumeurs du foie/métabolisme , Antigène AC133/métabolisme , Actines/métabolisme , Animaux , Arginase/métabolisme , Carcinome hépatocellulaire/génétique , Carcinome hépatocellulaire/anatomopathologie , Alimentation riche en graisse , Modèles animaux de maladie humaine , Régulation de l'expression des gènes tumoraux , Antigènes CD44/génétique , Antigènes CD44/métabolisme , Interleukine-6/métabolisme , Kératine-19/métabolisme , Foie/métabolisme , Foie/anatomopathologie , Tumeurs du foie/génétique , Tumeurs du foie/anatomopathologie , Souris , Souris knockout , Cellules souches tumorales/métabolisme , Cellules souches tumorales/anatomopathologie , Récepteur au PDGF bêta/métabolisme , Facteur de transcription STAT-3/métabolisme , Transduction du signal/génétique , Protéines suppresseurs de tumeurs/génétique , Protéines suppresseurs de tumeurs/métabolisme , Régulation positive , Protéine à doigts de zinc Gli2/métabolisme , Alphafoetoprotéines/métabolismeRÉSUMÉ
BACKGROUND & AIMS: As a nicotinamide adenine dinucleotide-dependent deacetylase and a key epigenetic regulator, sirtuin 6 (SIRT6) has been implicated in the regulation of metabolism, DNA repair, and inflammation. However, the role of SIRT6 in alcohol-related liver disease (ALD) remains unclear. The aim of this study was to investigate the function and mechanism of SIRT6 in ALD pathogenesis. METHODS: We developed and characterized Sirt6 knockout (KO) and transgenic mouse models that were treated with either control or ethanol diet. Hepatic steatosis, inflammation, and oxidative stress were analyzed using biochemical and histological methods. Gene regulation was analyzed by luciferase reporter and chromatin immunoprecipitation assays. RESULTS: The Sirt6 KO mice developed severe liver injury characterized by a remarkable increase of oxidative stress and inflammation, whereas the Sirt6 transgenic mice were protected from ALD via normalization of hepatic lipids, inflammatory response, and oxidative stress. Our molecular analysis has identified a number of novel Sirt6-regulated genes that are involved in antioxidative stress, including metallothionein 1 and 2 (Mt1 and Mt2). Mt1/2 genes were downregulated in the livers of Sirt6 KO mice and patients with alcoholic hepatitis. Overexpression of Mt1 in the liver of Sirt6 KO mice improved ALD by reducing hepatic oxidative stress and inflammation. We also identified a critical link between SIRT6 and metal regulatory transcription factor 1 (Mtf1) via a physical interaction and functional coactivation. Mt1/2 promoter reporter assays showed a strong synergistic effect of SIRT6 on the transcriptional activity of Mtf1. CONCLUSIONS: Our data suggest that SIRT6 plays a critical protective role against ALD and it may serve as a potential therapeutic target for ALD. LAY SUMMARY: The liver, the primary organ for ethanol metabolism, can be damaged by the byproducts of ethanol metabolism, including reactive oxygen species. In this study, we have identified a key epigenetic regulator SIRT6 that plays a critical role in protecting the liver from oxidative stress-induced liver injury. Thus, our data suggest that SIRT6 may be a potential therapeutic target for alcohol-related liver disease.
Sujet(s)
Épigenèse génétique/génétique , Éthanol/métabolisme , Maladies alcooliques du foie/métabolisme , Stress oxydatif/génétique , Sirtuines/génétique , Sirtuines/métabolisme , Adulte , Animaux , Modèles animaux de maladie humaine , Régulation négative/génétique , Éthanol/effets indésirables , Stéatose hépatique/métabolisme , Femelle , Régulation de l'expression des gènes/génétique , Hépatocytes/métabolisme , Humains , Foie/métabolisme , Foie/anatomopathologie , Maladies alcooliques du foie/anatomopathologie , Mâle , Souris , Souris knockout , Adulte d'âge moyen , Espèces réactives de l'oxygène/métabolismeRÉSUMÉ
Patatin-like phospholipase domain-containing protein 3 (PNPLA3) is a lipid droplet-associated protein that has been shown to have hydrolase activity toward triglycerides and retinyl esters. The first evidence of PNPLA3 being associated with fatty liver disease was revealed by a genome-wide association study (GWAS) of Hispanic, African American, and European American individuals in the Dallas Heart Study back in 2008. Since then, numerous GWAS reports have shown that PNPLA3 rs738409[G] (148M) variant is associated with hepatic triglyceride accumulation (steatosis), inflammation, fibrosis, cirrhosis, and even hepatocellular carcinoma regardless of etiologies including alcohol- or obesity-related and others. The frequency of PNPLA3(148M) variant ranges from 17% in African Americans, 23% in European Americans, to 49% in Hispanics in the Dallas Heart Study. Due to high prevalence of obesity and alcohol consumption in modern societies, the PNPLA3(148M) gene variant and environment interaction poses a serious concern for public health, especially chronic liver diseases including alcohol-related liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). Therefore, PNPLA3(148M) variant is a potential therapeutic target for chronic liver disease in the rs738409 allele carriers. Currently, there is no approved drug specifically targeting the PNPLA3(148M) variant yet. With additional mechanistic studies, novel therapeutic strategies are expected to be developed for the treatment of the PNPLA3(148M) variant-associated chronic liver diseases in the near future.
RÉSUMÉ
Sestrins (Sesn1/2/3) belong to a small protein family that has versatile biological functions. In addition to initially characterized oxidoreductase activity, sestrins also have oxidoreductase-independent functions, including activation of AMP-activated protein kinase, inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) and activation of mTORC2. As these kinases are important for metabolic regulation, sestrins have a favorable profile as potential therapeutic targets for metabolic diseases such as diabetes. Recent data are in line with such a notion. In this editorial, I have attempted to provide a brief update on the major findings in regard to sestrins in metabolism.