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Age-Related Oxidative Stress Contributes to Excess Cholesterol in the Liver


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Posted 10 January 2019 - 11:22 AM


The presence of oxidative molecules in our biochemistry rises with aging, and cells react to this in many different ways. Internally to cells, this sort of damage can be rapidly repaired and brief bursts of oxidative molecule creation even serve as a signal for many necessary processes, such as the beneficial reactions to the stresses of exercise. Chronic oxidative stress produces dysfunction, however, whether that is via the production of toxic oxidized lipids or through through more direct means of causing cells to act in a harmful manner.

Chronic inflammation and mitochondrial dysfunction are two of the upstream causes of increased numbers of oxidative molecules. Among the downstream consequences can be found all sorts of detrimental cellular reactions, many of which are only poorly explored at best. The open access paper here is an example of the type. The best solution to this class of age-related problem is to go after the upstream causes, though mitochondrially targeted antioxidants appear to provide a beneficial suppression of oxidative stress in at least some situations.

The production of reactive oxygen species (ROS) is progressively increased in aging and is one of the key factors in cellular damage. It is known that ROS, including free radicals and peroxides, adversely affects cells and tissues and causes an imbalance in the biological system, contributing to the development of many aging-related diseases. In addition, oxidative stress plays an important role in hepatic disease. Aging increases fibrotic responses and is also associated with the development of a variety of liver diseases including nonalcoholic fatty liver disease and alcoholic liver disease. In particular, the prevalence of nonalcoholic fatty liver disease tends to increase with age, and thus, aging and lipid metabolism in the liver may be closely related. In addition, evidence suggests that increased oxidative stress due to various factors leads to increased lipid accumulation in the liver, while decreased oxidative stress has a lipid-lowering effect in hepatocytes.

Lipid supply to liver tissue consists of three main pathways: dietary intake, peripheral lipolysis, and de novo lipogenesis. Fatty liver occurs when the lipid supply exceeds the hepatic lipid removal. In many previous studies, triglyceride and cholesterol metabolism disorders and accumulation have been reported to be closely related to aging. For example, in the senescent-associated mouse, the cholesterol content in the liver was increased compared with control mice. In this study, we investigated the mechanisms for the increase in cholesterol accumulation during aging. We found that the increased ROS in aging plays an important role for the accumulation of cholesterol in the liver by increasing cholesterol uptake and cholesterol synthesis via increasing glucose uptake.

The mRNA expression of GLUT2, GK, SREBP2, HMGCR, and HMGCS, genes for cholesterol synthesis, was gradually increased in liver tissues during aging. When we treated HepG2 cells and primary hepatocytes with the ROS inducer, H2O2, lipid accumulation increased significantly compared to the case for untreated HepG2 cells. H2O2 treatment significantly increased glucose uptake and acetyl-CoA production, which results in glycolysis and lipid synthesis. Treatment with H2O2 significantly increased the expression of mRNA for genes related to cholesterol synthesis and uptake. These results suggest that ROS play an important role in altering cholesterol metabolism and consequently contribute to the accumulation of cholesterol in the liver during the aging process.

Link: https://doi.org/10.1111/acel.12895


View the full article at FightAging




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