HEPATIC 11BETA-HYDROXYSTEROID DEHYDROGENASE TYPE I and ATHEROSCLEROSIS RISK

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 796-817-Diabetes Genetics & Epidemiology
Translational
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-810
Kajal Manwani*, Tak Yung Man, Christopher J Kenyon, Ruth Andrew, Karen Elizabeth Chapman and Jonathan Robert Seckl
University of Edinburgh, Edinburgh, United Kingdom
Background: 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) converts inert glucocorticoids to active forms, amplifying intracellular glucocorticoid action. 11βHSD1 also catalyses the reduction of 7-ketocholesterol (7KC) to 7β-hydroxycholesterol (7βHC).  7KC may inhibit cholesterol biosynthesis (Brown et al., 2002). Alteration of cholesterol homeostasis is a major atherosclerotic risk factor. Improvement of metabolic syndrome and attenuation of atherosclerosis is observed in vulnerable rodent models when 11βHSD1 is knocked down or inhibited. Here, we have investigated whether 11βHSD1 influences hepatic cholesterol homeostasis in mice fed fat- or cholesterol-rich diets.

Methods: Male mice (5-6 week old, n=6-10/group): 11βHSD1-deficient (Hsd11b1-/-), transgenically overexpressing 11βHSD1 in liver (LOE) or wild-type (WT) were fed chow (C; 11% fat), high fat (HF; 58% fat) or western diet (WD; 38% fat + 0.2% cholesterol) for 12 weeks. Liver and fat depots were collected, RNA extracted and analysed by qPCR. Data (corrected for housekeeping genes) are mean ±SEM.

Results: Significantly decreased liver weight was observed for WD-fed Hsd11b1-/- mice (p<0.05), and reduced mesenteric fat was observed in HF-fed LOE mice compared to WT mice on the same diet (p<0.05). Compared to chow, WD decreased hepatic levels of mRNAs encoding SREBP2, HMG-CoA-reductase and HMG-CoA-synthase in WT mice as predicted, and in LOE mice (p<0.001). Hepatic LXRa mRNA was unaffected by diet in WT and Hsd11b1-/- mice (and did not differ in chow-fed mice between genotypes), but was increased in WD-fed LOE mice (WT, 100±3.46 vs. LOE, 178.48±6.21, p<0.05), as were the LXRa targets, Abgc5/8 (Abcg5: WT, 100±4.65 vs. LOE, 242.13±9.91, p<0.001; Abcg8: WT, 100±3.23 vs. LOE, 167.77±5.49, p<0.01).

Conclusion: These data do not support a role for hepatic 11βHSD1 in de novo cholesterol synthesis. However, increased hepatic Abcg5/8 expression in WD-fed LOE mice suggests hepatic 11βHSD1 promotes sterol efflux into the intestinal and biliary lumen, possibly meditated through higher Lxra expression. This suggests a role for hepatic 11βHSD1 in promoting biliary cholesterol secretion.

Nothing to Disclose: KM, TYM, CJK, RA, KEC, JRS

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm