Abstract
Our current understanding of oxysterol metabolism during different disease states such as obesity and dyslipidemia is limited. Therefore, the aim of this study was to determine the effect of diet-induced obesity on the tissue distribution of various oxysterols and the mRNA expression of key enzymes involved in oxysterol metabolism. To induce obesity, male C57BL/6J mice were fed a high fat-cholesterol diet for 24 weeks. Following diet-induced obesity, plasma levels of 4β-hydroxycholesterol, 5,6α-epoxycholesterol, 5,6β-epoxycholesterol, 7α-hydroxycholesterol, 7β-hydroxycholesterol, and 27-hydroxycholesterol were significantly (P < 0.05) increased. In the liver and adipose tissue of the obese mice, 4β-hydroxycholesterol was significantly (P < 0.05) increased, whereas 27-hydroxycholesterol was increased only in the adipose tissue. No significant changes in either hepatic or adipose tissue mRNA expression were observed for oxysterol synthesizing enzymes 4β-hydroxylase, 27-hydroxylase, or 7α-hydroxylase. Hepatic mRNA expression of SULT2B1b, a key enzyme involved in oxysterol detoxification, was significantly (P < 0.05) elevated in the obese mice. Interestingly, the appearance of the large HDL1 lipoprotein was observed with increased oxysterol synthesis during obesity. In diet-induced obese mice, dietary intake and endogenous enzymatic synthesis of oxysterols could not account for the increased oxysterol levels, suggesting that nonenzymatic cholesterol oxidation pathways may be responsible for the changes in oxysterol metabolism.
Highlights
During obesity and insulin resistance, increased adipocyte lipolysis paired with an inability of the fat cell to expand further to store lipid promotes excess ectopic lipid deposition, a major contributor to the development of cardiometabolic diseases [1]
Despite a 6.8% greater percent lipid mass in the adipose tissue in the high fat-cholesterol (HFC) group, no significant difference (P = 0.160) between the percentage of lipid mass was observed; after adjusting for cellular protein levels the HFC diet resulted in significantly greater cholesterol (P = 0.005) and triglyceride (P = 0.011) concentrations compared to normal control diet (ND) (Table 1)
We have demonstrated that obesity induced by a HFC diet resulted in markedly increased concentrations of both enzymatically and nonenzymatically derived oxysterols in the circulation as well as hepatic and adipose tissues
Summary
During obesity and insulin resistance, increased adipocyte lipolysis paired with an inability of the fat cell to expand further to store lipid promotes excess ectopic lipid deposition (i.e., lipotoxicity), a major contributor to the development of cardiometabolic diseases [1]. Lipotoxicity generally refers to cellular injury and death caused by free fatty acids (FFA) and related-lipid metabolites [1]. Cholesterol and its oxygenated species (oxysterols) add further to the complexity of the identification of lipotoxic species that affect the regulation of lipid and glucose metabolism, inflammation, endoplasmic reticulum (ER) stress, apoptosis, and necrosis [2]. The hepatic pools of FFA and cholesterol increase significantly, thereby promoting a cytotoxic environment [1]. Increased FFA oxidation can lead to the accumulation of reactive oxygen species (ROS) due to a reduced endogenous antioxidant capacity observed with nonalcoholic fatty liver disease [1]
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