ABCA1 plays no role in the centripetal movement of cholesterol from peripheral tissues to the liver and intestine in the mouse

Abstract

This study uses the mouse to explore the role of ABCA1 in the movement of this cholesterol from the peripheral organs to the endocrine glands for hormone synthesis and liver for excretion. The sterol pool in all peripheral organs was constant and equaled 2,218 and 2,269 mg/kg, respectively, in abca1 1/1 and abca1 2/2 mice. Flux of cholesterol from these tissues equaled the rate of synthesis plus the rate of LDL-cholesterol uptake and was 49.9 mg/day/kg in control animals and 62.0 mg/day/kg in abca1 2/2 mice. In the abca1 1/1 animals, this amount of cholesterol moved from HDL into the liver for excretion. In the abca1 2/2 mice, the cholesterol from the periphery also reached the liver but did not use HDL. Fecal excretion of cholesterol was just as high in abac1 2/2 mice (198 mg/day/kg) as in the abac1animals (163 mg/day/kg), although the abac1 2/2 mice excreted relatively more neutral than acidic sterols. This study established that ABCA1 plays essentially no role in the turnover of cholesterol in peripheral organs or in the centripetal movement of this sterol to the endocrine glands, liver, and intestinal tract for excretion.-Xie, C., S. D. Turley, and J. M. Dietschy. ABCA1 plays no role in the centripetal movement of cholesterol from peripheral tissues to the liver and intestine in the mouse. J. Lipid Res. 2009Res. . 50: 1316Res. -1329

In vivo tissue cholesterol efflux is reduced in carriers of a mutation in APOA1

“…Also, apoA-Idefi cient mice displayed a reduced 3 H-cholesterol fl ux from intraperitoneally injected 3 H-cholesterol-loaded macrophages through plasma toward the liver and into the feces ( 29,32 ). However, these results have been disputed by other studies in apoA-I-defi cient mice, indicating that apoA-I does not determine centripetal cholesterol fl ux to either the liver or the feces ( 12,13,33 ).…”

“…However, very few studies have addressed in vivo measurements of the RCT pathway in humans. Such studies are highly relevant, considering the current confl icting results regarding the role of HDL in RCT in murine studies (10)(11)(12)(13)(14), as well as in human studies of fecal sterol excretion (FSE) (15)(16)(17). Major hurdles to resolve this ongoing debate pertain to the complex nature of cholesterol metabolism and accordingly to the methodological complexity of quantifying in vivo cholesterol fl uxes in humans.…”

Insig Proteins Mediate Feedback Inhibition of Cholesterol Synthesis in the Intestine

“…These findings highlight key similarities and differences in the physiologic regulation of SREBP-2 in liver and intestine, the two organs responsible for over 70% of sterol synthesis in mice (10). In the liver, SREBP-2 is highly expressed and actively processed so long as animals are fed a low cholesterol diet.…”

Scap is required for sterol synthesis and crypt growth in intestinal mucosa

“…Primers for mouse leucine-rich repeat containing G protein-coupled receptor 5 (LGR5) and olfactomedin 4 (OLFM1) organism. Our prior studies investigated the role of the SREBP pathway in the intestine, which is quantitatively the second most important organ of sterol synthesis in rodents, behind the liver ( 5,8 ). A critical role for SREBPs in the maintenance of sterol homeostasis in the intestine was suggested by our fi nding that ezetimibe, a cholesterollowering drug that blocks intestinal cholesterol uptake by inhibiting the luminal cholesterol transporter NiemannPick C1-like 1 protein (NPC1L1), caused major increases in intestinal nuclear SREBP-2 and HMG-CoA reductase (HMGR), the enzyme that catalyzes the rate-determining step of the sterol biosynthetic pathway ( 9 ).…”