Complex feedback regulation of bile acid synthesis in the hamster: The role of newly synthesized cholesterol

Afdhal

Journal of Lipid Research

2006

We explored whether there is an ''estrogen-ERa-SREBP-2'' (for estrogen-estrogen receptor subtype a-sterolregulatory element binding protein-2) pathway for regulating hepatic cholesterol biosynthesis in ovariectomized AKR mice treated with 17b-estradial (E 2 ) at 6 mg/day or E 2 plus the antiestrogenic agent ICI 182,780 at 125 mg/day and on chow or fed a high-cholesterol (1%) diet for 14 days. To monitor changes in cholesterol biosynthesis and newly synthesized cholesterol secreted into bile, incorporation into digitonin-precipitable sterols in mice treated with 25 mCi of [ 3 H]water was measured in extracts of liver and extrahepatic organs 1 h later and in hepatic biles 6 h later. ERa upregulated SREBP-2, with resulting activation of SREBP-2-responsive genes in the cholesterol biosynthetic pathway. The E 2 -treated mice continued to synthesize cholesterol in spite of its excess availability from high dietary cholesterol, which reflects a loss in controlling the negative feedback regulation of cholesterol synthesis. These alterations augmented biliary cholesterol secretion and enhanced the lithogenicity of bile. However, these lithogenic effects of E 2 were fully blocked by ICI 182,780. We conclude that during estrogen treatment, more newly synthesized cholesterol determined by the estrogen-ERa-SREBP-2 pathway is secreted into bile, leading to biliary cholesterol hypersecretion. These studies provide insights into therapeutic approaches to cholesterol gallstones in high-risk subjects, especially those exposed to high levels of estrogen.-Wang, H. H., N. H. Afdhal, and D. Q-H. Wang. Overexpression of estrogen receptor a increases hepatic cholesterogenesis, leading to biliary hypersecretion in mice. J. Lipid Res. 2006. 47: 778-786.

Section: Discussionsupporting

confidence: 92%

“…Biliary cholesterol secretion derives from either dietary or newly synthesized cholesterol or both (42)(43)(44)(45). Obviously, in an animal receiving no dietary cholesterol, all biliary cholesterol must ultimately be derived from de novo synthesis.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of estrogen receptor α increases hepatic cholesterogenesis, leading to biliary hypersecretion in mice

Afdhal

Journal of Lipid Research

2006

“…1,8,9 Because only a small fraction (5%-20%) of biliary cholesterol may be derived from de novo synthesis, [10][11][12] the bulk must be supplied by lipoproteins. Emerging evidence suggests that HDL plays a role for biliary cholesterol secretion, not only in small rodents (e.g., mice) carrying plasma cholesterol mainly in HDL, but also in humans where most of the cholesterol is transported in LDL.…”

mentioning

confidence: 99%

Biliary cholesterol hypersecretion in gallstone-susceptible mice is associated with hepatic up-regulation of the high-density lipoprotein receptor SRBI

Fuchs¹,

Ivandic

Müller³

et al. 2001

Hepatology

Enhanced hepatocellular trafficking of cholesterol to the bile canaliculus and cholesterol hypersecretion appears critical for gallstone formation. Therefore, we studied in more detail the hepatic cholesterol transport pathways in a mouse model of cholesterol gallstone disease. Biliary lipid secretion rates, plasma lipoprotein levels, hepatic expression of lipoprotein receptors, lipid regulatory enzymes, and putative cholesterol transporting proteins were analyzed in gallstone-susceptible C57L/J and gallstone-resistant AKR/J mice, which were fed a lithogenic diet. Biliary cholesterol hypersecretion in C57L mice was associated with decreased plasma high-density lipoprotein (HDL) cholesterol levels and significant hepatic induction of the HDL receptor (SRBI) and cholesteryl ester hydrolase. In response to the lithogenic diet, fatty-acid binding protein of liver (FABPL) was markedly induced in both mouse strains. Caveolin 1 was elevated only in plasma membranes of gallstone-susceptible C57L mice, which also failed to down-regulate cholesterol synthesis. These data suggest a role of the reverse cholesterol transport pathway for genetically determined gallstone susceptibility in the mouse. (HEPATOLOGY 2001;33: 1451-1459.)

“…In contrast to studies by Hellerstein and Neese 39 and our own previous work, 9 [1][2][3][4][5][6][7][8][9][10][11][12][13] C]acetate was infused intraduodenally and not intravenously. Because of the preferential hepatic clearance of acetate from portal blood, 35,40 the dose could be reduced to one third of the amount given intravenously, and both experimental procedures resulted in comparable cytosolic [ 13 C]acetate enrichments.…”

Section: Discussionmentioning

confidence: 99%

“…In rats and hamsters the amount of newly synthesized cholesterol secreted into bile amounts to 8% to 18% and 2% to 5%, respectively. [3][4][5][6] In humans, most of the indirect evidence using standard radioisotope kinetics supported that 20% of biliary cholesterol were derived from de novo synthesis, 7 the majority being preformed cholesterol supplied by high-density lipoprotein cholesterol. 8 We have recently shown that the mass isotopomer distribution analysis (MIDA) technique allows for the direct measurement of the 4% to 5% of newly synthesized cholesterol formed from [ 13 C]acetate in bile and also that a significantly higher proportion of de novo cholesterol is secreted into bile as opposed to plasma in healthy individuals' circulation.…”

mentioning

confidence: 99%

The pravastatin-induced decrease of biliary cholesterol secretion is not directly related to an inhibition of cholesterol synthesis in humans

et al. 1999

Self Cite

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to suppress biliary cholesterol secretion and saturation. It remains unproven whether this is mediated by inhibition of cholesterol synthesis. Therefore, the effect of a long-term administration of pravastatin on cholesterogenesis and on biliary lipid secretion was investigated in seven healthy volunteers. Placebo or 40 mg of pravastatin were taken daily at bedtime for 5 weeks using a double-blind crossover design. During the last week, 12 hours after the last drug intake 0.04 mmol [1-13 C]acetate/kg · h and 0.5 g polyethylene glycol 4,000/h were infused intraduodenally for 15 hours. Plasma and duodenal bile samples were collected hourly. Thereafter, the decay of [ 13 C]labeled plasma cholesterol was measured during the following 3 days. The fractional and absolute syntheses of plasma and biliary cholesterol were determined by gas chromatography mass spectrometry using mass isotopomer distribution analysis. At the end of the pravastatin period plasma total and low-density lipoprotein (LDL) cholesterol had decreased by 20% and 24%, respectively. Similarly, pravastatin suppressed biliary secretion rates of cholesterol, total bile acids and phospholipids (P F .05) by 46%, 36%, and 51%. As a consequence, cholesterol saturation index remained unchanged. However, fractional syntheses of cholesterol were comparable (P G .05) on placebo compared with pravastatin with 3.1% versus 4.0% in plasma and 4.3% versus 5.2% in bile after 15 hours, respectively. The mean absolute synthesis rates amounted to 0.3 mg/kg/h on placebo versus 0.4 on pravastatin (P G .05). In conclusion, the pravastatin-induced reduction of biliary cholesterol secretion is not directly related to an inhibition of cholesterol synthesis. (HEPATOLOGY 1999;30:14-20.)A variety of defects are realized to explain the pathogenesis of cholesterol gallstone formation, including cholesterol supersaturation as well as gallbladder hypomotility, rapid nucleation, and a mucin hypersecretion. Most likely a sustained cholesterol supersaturation of bile 1 owing to hepatic hypersecretion of cholesterol 2 stands at the beginning of this process. In animal studies the origin of biliary secreted cholesterol has been well defined. In rats and hamsters the amount of newly synthesized cholesterol secreted into bile amounts to 8% to 18% and 2% to 5%, respectively. [3][4][5][6] In humans, most of the indirect evidence using standard radioisotope kinetics supported that 20% of biliary cholesterol were derived from de novo synthesis, 7 the majority being preformed cholesterol supplied by high-density lipoprotein cholesterol. 8 We have recently shown that the mass isotopomer distribution analysis (MIDA) technique allows for the direct measurement of the 4% to 5% of newly synthesized cholesterol formed from [ 13 C]acetate in bile and also that a significantly higher proportion of de novo cholesterol is secreted into bile as opposed to plasma in healthy individuals' circulation. 9 Thus, it seems tha...