11β-Hydroxysteroid dehydrogenase type one (11β-HSD1) converts inert glucocorticoids to active forms, amplifying intracellular glucocorticoid action. 11β-HSD1 also catalyses the reduction of seven-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. 11β-HSD1 deficiency/inhibition is atheroprotective in animal models, despite only modest changes in plasma cholesterol levels. Here, we have investigated whether 11β-HSD1 influences hepatic cholesterol homeostasis in mice fed fat or cholesterol-rich diets.
Male mice (56-week-old, n=610/group): 11β-HSD1-deficient (Hsd11b1−/−), transgenically overexpressing 11β-HSD1 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 ±S.E.M..
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 LXRα 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 LXRα 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).
These data do not support a role for hepatic 11β-HSD1 in de novo cholesterol synthesis. However, increased hepatic Abcg5/8 expression in WD-fed LOE mice suggests hepatic 11β-HSD1 promotes sterol efflux into the intestinal and biliary lumen, possibly meditated through higher Lxrα expression. This suggests a role for hepatic 11β-HSD1 in promoting biliary cholesterol secretion.
Declaration of funding: This work was supported by the Wellcome Trust Programme (grant number WT083184). K Manwani is a PhD student sponsored by University of Edinburgh/SORSAS scholarships.