Dietary cholesterol and downregulation of cholesterol 7 alpha-hydroxylase and cholesterol absorption in African green monkeys.

Rudel, Lawrence L.; Deckelman, C; Wilson, Martha D.; Scobey, Martin; Anderson, Richard A.

doi:10.1172/jci117255

Cited by 97 publications

(47 citation statements)

References 40 publications

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“…Studies in mice show that many sterol regulatory element-binding proteins and liver X receptor-sensitive genes can be coordinately regulated at the transcriptional level in response to dietary cholesterol (7,8). In contrast to what has been described for rodents (7), liver X receptormediated regulation of the cholesterol 7␣-hydroxylase gene does not explain the down-regulation of this enzyme by dietary cholesterol in primates (9). Instead, cholesterol esterification enzymes are candidate sites for regulation.…”

mentioning

confidence: 88%

Primates Highly Responsive to Dietary Cholesterol Up-regulate Hepatic ACAT2, and Less Responsive Primates Do Not

Rudel

Davis

Sawyer

et al. 2002

Journal of Biological Chemistry

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The role of liver acyl-CoA:cholesterol acyltransferase 2 (ACAT2), earlier shown to be the principal ACAT enzyme within primate hepatocytes, as a regulator of the hypercholesterolemia induced by dietary cholesterol was studied. At the end of low and high cholesterol diet periods, liver biopsies were taken from cynomolgus monkeys, a species highly responsive to dietary cholesterol, and less responsive African green monkeys. Liver cholesterol and cholesteryl ester concentrations were highest in cynomolgus monkeys fed cholesterol, despite the fact that in order to induce equivalent hypercholesterolemia, dietary cholesterol levels were 50% lower than was fed to green monkeys. Hepatic cholesteryl oleate secretion rate, measured during liver perfusion as an indicator of ACAT activity, was significantly higher in cynomolgus monkeys. Liver microsomal ACAT activity was 2-3-fold higher in cynomolgus monkeys than in green monkeys. The responses of ACAT2 were compared with those of ACAT1 that is found primarily in Kupffer cells. ACAT2 protein mass was significantly correlated to microsomal total ACAT activity in both species; ACAT1 mass was less well correlated. Dietary cholesterol induced a significant 3-fold increase of ACAT2 protein mass in cynomolgus monkeys, a much greater increase than was found for mRNA abundance; neither ACAT2 mRNA nor protein was diet-responsive in green monkeys. In cynomolgus monkeys but not in green monkeys, liver free cholesterol concentrations were elevated when cholesterol was fed and were correlated with ACAT2 protein levels. The data suggest a mechanism whereby the elevation of hepatic free cholesterol concentrations by dietary cholesterol, seen only in cynomolgus monkeys, resulted in higher ACAT2 protein levels in hepatocytes, either through increased production or stabilization of the protein. Regulation of ACAT2 gene transcription was not a factor.

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confidence: 88%

Primates Highly Responsive to Dietary Cholesterol Up-regulate Hepatic ACAT2, and Less Responsive Primates Do Not

Rudel

Davis

Sawyer

et al. 2002

Journal of Biological Chemistry

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“…Ϫ/Ϫ Mice Lack Induction of CYP7A1 Expression (12) and rabbits (35). The mechanism for this decrease is not immediately apparent, particularly in primates, although it has been suggested (36) that, in rabbits, there is induction of CYP7A1 with an increase in bile acid pool size that overrides the cholesterol effect and results in lowering of CYP7A1 expression through the FXR-mediated pathway.…”

Section: Cyp7a1mentioning

confidence: 99%

“…LXR induces transcription of a number of other genes involved in cholesterol disposition (11). In some species, cholesterol feeding leads to a decrease in CYP7A1 levels (12,13). In these cases, the increase in bile acid synthesis induced by cholesterol feeding may ultimately lead to suppression of CYP7A1 because of an expanded bile acid pool.…”

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confidence: 99%

Mice Expressing the Human CYP7A1 Gene in the Mouse CYP7A1 Knock-out Background Lack Induction of CYP7A1 Expression by Cholesterol Feeding and Have Increased Hypercholesterolemia When Fed a High Fat Diet

Chen

Levy-Wilson

Goodart

et al. 2002

Journal of Biological Chemistry

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Cholesterol 7␣-hydroxylase (CYP7A1) catalyzes the rate-limiting step in the pathway responsible for the formation of the majority of bile acids. Transcription of the gene is regulated by the size of the bile acid pool and dietary and hormonal factors. The farnesoid X receptor and the liver X receptor (LXR) are responsible for regulation by bile acids and cholesterol, respectively. To study the effects of dietary cholesterol and fat upon expression of the human CYP7A1 gene, mice were generated by crossing transgenic mice carrying the human CYP7A1 gene with mice that were homozygous knockouts (CYP7A1 ؊/؊ ). The mice (mCYP7A1 ؊/؊ /hCYP7A1) expressed the human gene at much higher levels than did the transgenics bred in the wild-type background. A diet containing 1% cholic acid reduced the expression of the human gene in mCYP7A1 ؊/؊ /hCYP7A1 mice to undetectable levels. Cholestyramine (5%) increased the level of expression of the human gene and the mouse gene. Thus, farnesoid X receptor-mediated regulation was preserved. A diet containing 2% cholesterol increased expression of the mouse gene in wild-type mice, but it did not affect expression of the human gene in mCYP7A1 ؊/؊ /hCYP7A1 mice. None of the diets altered the serum cholesterol or triglyceride levels in these mice; 1% cholic acid caused a redistribution of cholesterol from the high density lipoprotein to the low density lipoprotein density in the humanized mice but not in wild-type mice. A diet containing 30% saturated fat and 2% cholesterol caused a decrease in CYP7A1 levels in mCYP7A1 ؊/؊ /hCYP7A1 mice. The serum cholesterol levels rose in all mice fed this diet. The increase was greater in the mCYP7A1 ؊/؊ /hCYP7A1 mice. Together, these data suggest that the lack of an LXR element in the region from ؊56 to ؊49 of the human CYP7A1 promoter may account for some of the differences in response to diets between humans and rodents.Cholesterol is a lipid molecule that plays unique and specific roles in cellular membrane function and embryonic development. It also serves as a precursor for the synthesis of steroid hormones and bile acids. Accordingly, a sophisticated system has evolved to ensure its availability to cells. The liver plays a central role in coordinating many of the components of this process. The accumulation of excess cholesterol in blood vessels leads to atherosclerosis and its accumulation in the bile leads to gallstones. Humans, in contrast to rodents, are highly susceptible to these conditions. Hepatic cholesterol homeostasis is controlled by the rate of cholesterol entry to the liver from dietary and endogenous lipoproteins, as well as by the rate of synthesis of new cholesterol relative to the rate of hepatic lipoprotein secretion, the rate of cholesterol degradation to bile acids, and the rate of excretion of the intact molecule into the bile. These various processes are modulated by the levels of the enzymes catalyzing the rate-limiting steps of each process. An important determinant of the level of these proteins is the rate of transcripti...

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“…It has been reported that rodents have a very hydrophilic bile acid pool, which is less potent in activation of FXR; thus, the LXRα could function as an important regulator of CYP7A1 in mice (Chiang et al, 2001). In contrast, CYP7A1 expression was down-regulated by a high-cholesterol diet in African green monkeys (Rudel et al, 1994) and in rabbits (Xu et al, 2003), since the inhibitory effect of FXR may override the stimulatory effect of LXRα. There are another Figure 7.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of acyl-coenzyme A:cholesterol acyltransferase stimulates cholesterol efflux from macrophages and stimulates farnesoid X receptor in hepatocytes

Jang

Park

et al. 2008

Exp Mol Med

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We investigated the mechanism of spontaneous cholesterol efflux induced by acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibition, and how an alteration of cholesterol metabolism in macrophages impacts on that in HepG2 cells. Oleic acid anilide (OAA), a known ACAT inhibitor reduced lipid storage substantially by promotion of cholesterol catabolism and repression of cholesteryl ester accumulation without further increase of cytotoxicity in acetylated low-density lipoprotein-loaded THP-1 macrophages. Analysis of expressed mRNA and protein revealed that cholesterol 7α-hydroxylase (CYP7A1), oxysterol 7α-hydroxylase (CYP7B1), and cholesterol 27-hydroxylase (CYP27) were highly induced by ACAT inhibition. The presence of a functional cytochrome P450 pathway was confirmed by quantification of the biliary cholesterol mass in cell monolayers and extracelluar medium. Notably, massively secreted biliary cholesterol from macrophages suppressed the expression of CYP7 proteins in a farnesoid X receptor (FXR)-dependent manner in HepG2 cells. The findings reported here provide new insight into mechanisms of spontaneous cholesterol efflux, and suggest that ACAT inhibition may stimulate cholesterol-catabolic (cytochrome P450) pathway in lesion-macrophages, in contrast, suppress it in hepatocyte via FXR induced by biliary cholesterol (BC).

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Dietary cholesterol and downregulation of cholesterol 7 alpha-hydroxylase and cholesterol absorption in African green monkeys.

Cited by 97 publications

References 40 publications

Primates Highly Responsive to Dietary Cholesterol Up-regulate Hepatic ACAT2, and Less Responsive Primates Do Not

Primates Highly Responsive to Dietary Cholesterol Up-regulate Hepatic ACAT2, and Less Responsive Primates Do Not

Mice Expressing the Human CYP7A1 Gene in the Mouse CYP7A1 Knock-out Background Lack Induction of CYP7A1 Expression by Cholesterol Feeding and Have Increased Hypercholesterolemia When Fed a High Fat Diet

Inhibition of acyl-coenzyme A:cholesterol acyltransferase stimulates cholesterol efflux from macrophages and stimulates farnesoid X receptor in hepatocytes

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