FXR activation promotes intestinal cholesterol excretion and attenuates hyperlipidemia in SR‐B1‐deficient mice fed a high‐fat and high‐cholesterol diet

Abstract

Obeticholic acid (OCA) activates the farnesoid X receptor (FXR) to lower circulating total cholesterol (TC) and high density lipoprotein‐cholesterol (HDL‐C) concentrations and to stimulate fecal cholesterol excretion in mice by increasing hepatic SR‐B1 expression. Here we show that hepatic SR‐B1 depletion by an adenovirus expressing Sr‐b1 shRNA (Ad‐shSR‐B1) attenuated these beneficial effects of OCA in mice on a chow diet. The mRNA levels of ABC cholesterol transporter genes (Abca1, Abcg1, Abcg5, and Abcg8) were unchanged in the liver of hepatic SR‐B1‐depleted mice regardless of OCA treatment; however, a modest increase in Abca1, Abcg5, and Abcg8 mRNA levels was observed in the ileum of vehicle‐treated control mice and Abca1 and Abcg8 mRNA levels were increased more by OCA administration. OCA treatment of Sr‐b1 knock out (KO) mice (Sr‐b1‐/‐) fed a normal chow diet (NCD) displayed a similar lack of transhepatic cholesterol movement, as well as a modest increase in the levels of ileum cholesterol transporter expression. However, OCA treatment of Sr‐b1 KO mice fed a cholesterol‐enriched diet reduced circulating cholesterol and increased fecal cholesterol output to comparable degrees to that of wild‐type (WT) mice, and these effects were accompanied by substantial elevations of mRNA levels of Abca1, Abcg1, Abcg5, and Abcg8 in the ileum of Sr‐b1 KO mice. Our studies suggest that FXR activation stimulates intestinal cholesterol excretion and reduces diet‐induced hyperlipidemia through increased expression of ileal cholesterol transporters when hepatic SR‐B1‐mediated cholesterol movement is absent.

The Effects of a High-Fat/Cholesterol Diet on the Intestine of Rats Were Attenuated by Sparassis latifolia Polysaccharides

“…However, compared with the HFC group, SLPs significantly decreased the expressions of NPC1L1, ACAT2 and MTP mRNA in a dose-dependent manner and the protein levels of NPC1L1, ACAT2and MTP were remarkably down-regulated in the HD group, supported by the previous report (29). In addition, our results also indicated that the mRNA of ABCG8 in the HD groups was overexpressed compared with the HFC group, which was consistent with previous report (30). It is established that cholesterol excretion raised by increasing the expression of ABCG8 genes (30).…”

“…In addition, our results also indicated that the mRNA of ABCG8 in the HD groups was overexpressed compared with the HFC group, which was consistent with previous report (30). It is established that cholesterol excretion raised by increasing the expression of ABCG8 genes (30). It is well known, in physiological conditions, there are some transport pathways for nutrition and endogenous substances to traverse the intestinal epithelium.…”

Impacts of Bacillus subtilis JQ61816 on lipid panel and expression of genes involved in cholesterol metabolism in hypercholesterolemic rats

“…In the current study, these effects were observed in BS group. On the other hand, FXR activation is shown to be effective in intestinal cholesterol excretion and hyperlipidemia attenuation [50]. It seems that the excretion of intestinal cholesterol may lead to a decrease in blood cholesterol levels.…”

Strategies to gain novel Alzheimer’s disease diagnostics and therapeutics using modulators of ABCA transporters

“… 414 In addition, the sterane derivative and farnesoid-X-receptor (FXR) activator obeticholic acid induced Abca1 mRNA levels in vitro in the ileum of Srb1 -deficient C57BL/6 mice. 415 In THP-1 macrophages, the sterane-like maslinic acid induced ABCA1 mRNA levels, paralleled with an increased cholesterol efflux from these cells. 390 Finally, the Salvia miltiorrhiza -derived tanshindiol C was demonstrated to induce peroxiredoxin 1 mRNA ( Prdx1 ) and protein (PRDX1) content in murine RAW264.7 cells.…”

“…Several in vivo studies demonstrated that modulators of ABCA transporters, in particular ABCA1, have systemic effects. 231 , 249 , 250 , 253 , 271 , 275 , 289 , 293 , 297 , 330 , 335 , 344 , 350 , 361 , 362 , 366 , 368 - 370 , 376 , 378 , 383 , 410 , 415 , 417 - 419 , 425 , 431 , 436 , 448 However, the vast majority of these modulators were regulators, 231 , 250 , 253 , 271 , 297 , 330 , 335 , 344 , 350 , 361 , 362 , 366 , 368 - 370 , 376 , 378 , 383 , 410 , 415 , 417 - 419 , 425 , 431 , 436 , 448 specifically inducers, 250 , 253 , 271 , 297 , 330 , 344 , 361 , 362 , 366 , 368 - 370 , 376 , 378 ...…”