Research Article: Reactive oxygen species‐induced changes in glucose and lipid metabolism contribute to the accumulation of cholesterol in the liver during aging

Date Published: January 04, 2019

Publisher: John Wiley and Sons Inc.

Author(s): Eunhui Seo, Hwansu Kang, Hojung Choi, Woohyuk Choi, Hee‐Sook Jun.


Aging is a major risk factor for many chronic diseases due to increased vulnerability to external stress and susceptibility to disease. Aging is associated with metabolic liver disease such as nonalcoholic fatty liver. In this study, we investigated changes in lipid metabolism during aging in mice and the mechanisms involved. Lipid accumulation was increased in liver tissues of aged mice, particularly cholesterol. Increased uptake of both cholesterol and glucose was observed in hepatocytes of aged mice as compared with younger mice. The mRNA expression of GLUT2, GK, SREBP2, HMGCR, and HMGCS, genes for cholesterol synthesis, was gradually increased in liver tissues during aging. Reactive oxygen species (ROS) increase with aging and are closely related to various aging‐related diseases. 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.

Partial Text

Aging refers to a state in which homeostasis can no longer be maintained due to structural changes or dysfunction and the organism becomes vulnerable to external stress or damage (Lopez‐Otin, Blasco, Partridge, Serrano, & Kroemer, 2013). Aging is a major risk factor for most chronic diseases such as cerebrovascular disease, neurodegeneration, chronic obstructive sleep apnea, cancer, and diabetes (Bonomini, Rodella, & Rezzani, 2015).

Aging is highly related to the disorders of glucose and lipid metabolism. (Mc Auley & Mooney, 2015; Salmon, 2012), and hepatic lipid accumulation can contribute to aging‐related diseases, including fatty liver, liver cirrhosis, and metabolic syndrome (Sheedfar, Biase, Koonen, & Vinciguerra, 2013). Hepatic lipid deposition is strictly controlled by a variety of factors including dietary lipid intake, circulating lipid levels, glucose uptake, lipid synthesis, hepatic lipid oxidation, and liver lipid release. (Gong, Tas, Yakar, & Muzumdar, 2017). Therefore, changes in liver lipid content might be due to the changes in glucose and lipid metabolism. The mechanisms for TG accumulation in the liver in aging have been extensively studied. (Guan et al., 2013; Xiong et al., 2014). However, there has been little research on the hepatic accumulation of cholesterol following aging.

The authors have declared that no competing interests exist.

The authors’ responsibilities were as follows—H.‐S.J. conceived and designed the study, and wrote the manuscript. E.S. contributed to the design of the study, performed the experiments, and wrote the manuscript. H.K., H.C., and W.C. performed the experiments.




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