Selective glucocorticoid receptor modulation prevents and reverses non-alcoholic fatty liver disease in male mice.

Selective glucocorticoid receptor modulation prevents and reverses non-alcoholic fatty liver disease in male mice. Endocrinology. 2018 Oct 12;: Authors: Koorneef LL, van den Heuvel JK, Kroon J, Boon MR, 't Hoen PAC, Hettne KM, van de Velde NM, Kolenbrander KB, Streefland TCM, Mol IM, Sips HCM, Kielbasa SM, Mei H, Belanoff JK, Pereira AM, Oosterveer MH, Hunt H, Rensen PCN, Meijer OC Abstract Non-alcoholic fatty liver disease (NAFLD) medication is an unmet need. Glucocorticoid stress hormones (GC) drive fat metabolism in the liver, but both full blockade and full stimulation of GC signaling aggravate NAFLD pathology. We investigated the efficacy of selective glucocorticoid receptor (GR) modulator CORT118335, that recapitulates only a subset of GC actions, in reducing liver lipid accumulation in mice. Male C57BL/6J mice received low-fat diet, or high-fat diet mixed with vehicle or CORT118335. Livers were analyzed histologically and for genome-wide mRNA expression. Functionally, hepatic long-chain fatty acid (LCFA) composition was determined by gas chromatography. We determined very-low-density-lipoprotein (VLDL) production by treatment with a lipoprotein lipase inhibitor after which blood was collected to isolate radiolabeled VLDL particles and ApoB proteins. CORT118335 strongly prevented and reversed hepatic lipid accumulation. Liver transcriptome analysis showed increased expression of GR target genes involved in VLDL production. Acco...
Source: Endocrinology - Category: Endocrinology Authors: Tags: Endocrinology Source Type: research