Sirt6 protects retinal ganglion cells and optic nerve from degeneration during aging and glaucoma.

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.

Depdc5 deficiency exacerbates alcohol-induced hepatic steatosis via suppression of PPARα pathway.

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.

Signal Transduction and Molecular Regulation in Fatty Liver Disease.

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. Remarkable progress has been made in the recent years in basic and translational research in the field of fatty liver disease.

Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping.

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.

PNPLA3-A Potential Therapeutic Target for Personalized Treatment of Chronic Liver Disease.

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.

Sesn3 deficiency promotes carcinogen-induced hepatocellular carcinoma via regulation of the hedgehog pathway.

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.

The epigenetic regulator SIRT6 protects the liver from alcohol-induced tissue injury by reducing oxidative stress in mice.

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.

The potential of sestrins as therapeutic targets for diabetes.

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.