The Influence of an Obesogenic Diet on Oxysterol Metabolism in C57BL/6J Mice

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.

Steroid biosynthesis in adipose tissue

“…In male C57BL/6J mice, GC-MS analysis showed the presence of 4β-hydroxycholesterol, 7α-hydroxycholesterol, 7β-hydroxycholesterol, 25-hydroxycholesterol, 27-hydroxycholesterol, 7-ketocholesterol, 5, 6α-epoxycholesterol, and 5,6β-epoxycholesterol in perigonadal adipose tissue (174). Consistent with the data from humans, local concentrations of 27-hydroxycholesterol and 4β-hydroxycholesterol in the adipose tissue of diet-induced obese mice were elevated by 2.5-and 7.5-fold, respectively (174). Taken together, adipose tissue may provide a sink for these lipophilic oxysterols, and the local synthesis or metabolism of oxysterols may be different in adipose tissue based on health and disease.…”

“…A different group has discovered cholesterol-5α, 6α-epoxide -another cholesterol derivative from autoxidation -in human omental and subcutaneous adipose tissue, and its concentration was 34% higher in omental fat (173). In male C57BL/6J mice, GC-MS analysis showed the presence of 4β-hydroxycholesterol, 7α-hydroxycholesterol, 7β-hydroxycholesterol, 25-hydroxycholesterol, 27-hydroxycholesterol, 7-ketocholesterol, 5, 6α-epoxycholesterol, and 5,6β-epoxycholesterol in perigonadal adipose tissue (174). Consistent with the data from humans, local concentrations of 27-hydroxycholesterol and 4β-hydroxycholesterol in the adipose tissue of diet-induced obese mice were elevated by 2.5-and 7.5-fold, respectively (174).…”

“…Although the cell or tissue sources from which 27HC originates have not yet been identified, excess adipose tissue seem to be a promising candidate that contributes to the induced 27HC level that occurs in obesity. A recent study conducted with rodents showed that the 27HC concentration in rat adipose tissue was induced with obesity (174). Information regarding the in vivo production and concentration of 27HC in human adipose tissue is still lacking.…”

The interaction between metabolism, cancer and cardiovascular disease, connected by 27-hydroxycholesterol

“…In addition to the abundance of cholesterol, CYP27A1 is also upregulated in atherosclerotic lesions [10,54], and its expression increases during monocyte to macrophage differentiation [55]. High cholesterol/fat diet increases plasma, hepatic and adipose levels of 27HC in mice [56]. 27HC is also locally produced as one of the major de novo cholesterol products in adipocytes and suppresses adipocyte differentiation, suggesting the prevention of the formation of new fat cells upon overfeeding with dietary cholesterol [57].…”

Streptococcal serum opacity factor promotes cholesterol ester metabolism and bile acid secretion in vitro and in vivo

“…Cell homogenates were assayed for protein, total cholesterol, free cholesterol, phospholipid and triglycerides. Samples for oxysterol and bile acid assays were lipid-extracted after addition of seven deuterium labeled oxysterol internal standards (Avanti Polar Lipids, Alabaster, AL), and processed for analysis as trimethylsilyl ether derivatives by gas chromatography-mass spectrometry (GC-MS) using a modification [17] of the isotope dilution method [18-20]. Ions used for analysis (m/z) appear in Supplemental Table 1.…”