Sterol 12alpha-hydroxylase Aggravates Dyslipidemia by Activating the Ceramide/mTORC1/SREBP1C Pathway via FGF21 and FGF15.

Title

Sterol 12alpha-hydroxylase Aggravates Dyslipidemia by Activating the Ceramide/mTORC1/SREBP1C Pathway via FGF21 and FGF15.

Creator

Pathak Preeti; Chiang John Y L

Publisher

Gene expression

Date

2019
2019-03

Description

Sterol 12alpha-hydroxylase (CYP8B1) is required for synthesis of cholic acid in the classic bile acid synthesis pathway and plays a role in dyslipidemia and insulin resistance. However, the mechanism of the involvement of Cyp8b1 in dyslipidemia and insulin resistance is not known. CYP8B1 mRNA and protein expression are elevated in diabetic and obese (db/db) mouse liver. In this study adenovirus-mediated transduction of CYP8B1 was used to study the effect of Cyp8b1 on lipid metabolism in mice. Results show that Ad-Cyp8b1 increased 12alpha-hydroxylated bile acids and induced sterol regulatory element binding protein 1c (Srebp1c)-mediated lipogenic gene expression. Interestingly, Ad-Cyp8b1 increased ceramide synthesis and activated hepatic mechanistic target of rapamycin complex 1 (mTORC1)-p70S6K signaling cascade and inhibited AKT/insulin signaling in mice. Ad-Cyp8b1 increased free fatty acid uptake into mouse primary hepatocytes. Ceramides stimulated S6K phosphorylation in both mouse and human primary hepatocytes. In high fat diet-fed mice, Ad-Cyp8b1 reduced fibroblast growth factor 21 (FGF21), activated intestinal farnesoid X receptor (FXR) target gene expression, increased serum ceramides, VLDL secretion, and LDL cholesterol. In high fat diet-induced obese (DIO) mice, Cyp8b1 ablation by adenovirus-mediated shRNA improved oral glucose tolerance, increased FGF21, and reduced liver triglycerides, inflammatory cytokine expression, nuclear localization of Srebp1c and phosphorylation of S6K. In conclusion, this study unveiled a novel mechanism linking CYP8B1 to ceramide synthesis and mTORC1 signaling in dyslipidemia and insulin resistance, via intestinal FXR-mediated induction of FGF15 and liver FGF21. Reducing cholic acid synthesis may be a potential therapeutic strategy to treat dyslipidemia and non-alcoholic fatty liver disease.

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Citation

Pathak Preeti; Chiang John Y L, “Sterol 12alpha-hydroxylase Aggravates Dyslipidemia by Activating the Ceramide/mTORC1/SREBP1C Pathway via FGF21 and FGF15.,” NEOMED Bibliography Database, accessed January 26, 2021, https://neomed.omeka.net/items/show/6326.

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