SUN-640 Deletion Of Adipose FXR In Mice Exacerbates Hepatic Fat Accumulation Upon Western Diet

Abstract

Disclosure: D.X. Yrigoyen Rosas: None. N. Dadlani: None. S. Anakk: None. W. Zhou: None. D. Molina Chaves: None. J. Amengual Terrasa: None.

Nuclear receptor Farnesoid X receptor (FXR) acts as a nutrient sensor, regulating lipids, amino acids, and glucose. Metabolic dysfunction-associated fatty liver disease (MAFLD) is on the rise and FXR ligand, obeticholic acid, was previously tested as a potential therapeutic. Recently, adipose-FxrKO mice were shown to exhibit altered glucose homeostasis. We independently generated adipose-FxrKO mice and examined the response to calorie-dense diets (either high fat or western diet). Here, we focused on the hepatic response of Ad-FxrKO mice to examine if loss of FXR in one organ affects the response in another. We hypothesize that adipose FXR signaling is necessary to protect against insulin resistance and hepatic lipid accumulation. To demonstrate this, male Ad-FxrKO and f/f Fxr control mice were used for this experiment. Each group consisted of 6-8 mice with a C57BL/6J genetic background and an age of 10-12 weeks. They were challenged with a normal chow (ChD), 60% high fat (HFD), or high fat/high sucrose western diet (WD) for 4 weeks to mimic obesogenic conditions and were weighed every week. All the diets were provided by Envigo. At the end of the diet period, they were sacrificed, and liver tissue was collected for histological, protein (Western blot) and gene expression (qPCR) analysis. Ad-FxrKO mice developed mild glucose intolerance upon diet challenges, but hepatic steatosis was severe in response to WD but not with HFD. Ectopic fat accumulation was similar between genotypes under the HFD. To understand this discrepancy in hepatic fat deposition between the two diets and genotypes, we examined the lipid metabolic genes in the liver. Lipid synthesis-related genes were downregulated upon HFD, but upregulated in WD irrespective of the genotypes. On the other hand, lipid breakdown-related genes were downregulated in the WD group, but upregulated in the HFD group in WT and Ad-FxrKO. Although at the transcript level we do not see any differences, we posit that insulin levels and sensitivity in the liver may be blunted in a diet-specific manner in Ad-FxrKO, which we are actively pursuing.

Presentation: Sunday, July 13, 2025