The mechanisms of and the interrelationship between bile acid and chylomicron-mediated regulation of hepatic cholesterol synthesis in the liver of the rat.

Nervi, Flavio

doi:10.1172/jci109015

Cited by 58 publications

(14 citation statements)

References 50 publications

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“…According to current concepts, cholesterol transported in chylomicron remnants is taken up by the liver and exerts feedback inhibition on HMG-CoA reductase, thereby controlling the endogenous synthesis of cholesterol (28). As expected, when large amounts of cholesterol were fed, HMG-CoA reductase activity declined fivefold (Table IV), supporting this hypothesis.…”

Section: Discussionsupporting

confidence: 75%

Comparative effects of cholestanol and cholesterol on hepatic sterol and bile acid metabolism in the rat.

Shefer¹,

Hauser²,

Salen³

et al. 1984

J. Clin. Invest.

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Abstract. Large amounts of cholestanol, the 5a-dihydro derivative of cholesterol are found in tissues of patients with the rare inherited sterol storage disease cerebrotendinous xanthomatosis. Although small amounts of cholestanol are present in virtually every tissue of normal man, little is known about its metabolism and effect on cholesterol and bile acid formation. The purpose of this study is to investigate the absorption and metabolism of cholestanol and its early effects on hepatic morphology and on the rate-limiting enzymes of cholesterol and bile acid biosynthesis. After 2 wk on a diet supplemented with 2% cholestanol, total liver sterol content increased by 48% (3.26 vs. 2.20 mg/g), and resulted in a significant rise in hepatic cholestanol concentration to 1.4 mg/g. However, cholestanol was less efficiently absorbed from the intestine than cholesterol and interfered with cholesterol absorption. Furthermore, hepatic hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase activity rose 2.6-fold (from 150.3 to 397.0 pmol/mg per min) during cholestanol feeding, and was associated with a marked proliferation of the smooth endoplasmic reticulum of the centrilobular areas. In addition, significant amounts of allocholic acid (16%) and allochenodeoxycholic acid (5%) were formed from cholestanol and excreted in the bile. These results show that cholestanol is absorbed from the intestine, interferes with cholesterol absorption, and is deposited in the liver. However, in contrast to cholesterol, cholestanol feeding was associated with a marked elevation of HMG-CoA

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Section: Discussionsupporting

confidence: 75%

Comparative effects of cholestanol and cholesterol on hepatic sterol and bile acid metabolism in the rat.

Shefer¹,

Hauser²,

Salen³

et al. 1984

J. Clin. Invest.

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“…It has been suggested that hepatic HMG-CoA reductase activity is mediated through chylomicron remnant pathway (39), and dietary cholesterol curbs hepatic cholesterol synthesis by Ͼ95% in the rat (40). Other studies (41) suggest a direct effect of bile acids on hepatic HMG-CoA reductase activity.…”

Section: Discussionmentioning

confidence: 99%

Effect of β-muricholic acid on the prevention and dissolution of cholesterol gallstones in C57L/J mice

Wang

Tazuma

2002

Journal of Lipid Research

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This study investigated whether ␤ -muricholic acid, a natural trihydroxy hydrophilic bile acid of rodents, acts as a biliary cholesterol-desaturating agent to prevent cholesterol gallstones and if it facilitates the dissolution of gallstones compared with ursodeoxycholic acid (UDCA). For gallstone prevention study, gallstone-susceptible male C57L mice were fed 8 weeks with a lithogenic diet (2% cholesterol and 0.5% cholic acid) with or without 0.5% UDCA or ␤ -muricholic acid. For gallstone dissolution study, additional groups of mice that have formed gallstones were fed chow with or without 0.5% ␤ -muricholic acid or UDCA for 8 weeks. One hundred percent of mice fed the lithogenic diet formed cholesterol gallstones. Addition of ␤ -muricholic acid and UDCA decreased gallstone prevalence to 20% and 50% through significantly reducing biliary secretion rate, saturation index, and intestinal absorption of cholesterol, as well as inducing phase boundary shift and an enlarged Region E that prevented the transition of cholesterol from its liquid crystalline phase to solid crystals and stones. Eight weeks of ␤ -muricholic acid and UDCA administration produced complete gallstone dissolution rates of 100% and 60% compared with the chow (10%). We conclude that ␤ -muricholic acid is more effective than UDCA in treating or preventing dietinduced or experimental cholesterol gallstones in mice. -Wang, D. Q-H., and S. Tazuma. Effect of ␤ -muricholic acid on the prevention and dissolution of cholesterol gallstones in C57L/J mice.

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“…This suggests that stimulation of synthesis is mediated by different mechanism(s). Cholestyramine enhances the removal of cholesterol solely as bile acids and depletes hepatocyte cholesterol in man (24), a change considered to be the major factor in stimulating hepatic cholesterol synthesis (38). In addition, the drug may stimulate intestinal cholesterol synthesis to some extent in man (39).…”

Section: Methodsmentioning

confidence: 99%

“…Inhibition of cholesterol absorption by neomycin, on the other hand, decreases the supply of absorbed cholesterol to the hepatocyte and should stimulate hepatic cholesterol synthesis (38). However, in the rat neomycin actually had no effect on hepatic cholesterolgenesis but almost doubled intestinal cholesterol synthesis from acetate and increased conversion of mevalonate to nonsaponifiable lipids other than cholesterol (8).…”

Section: Methodsmentioning

confidence: 99%

Effects of Neomycin Alone and in Combination with Cholestyramine on Serum Cholesterol and Fecal Steroids in Hypercholesterolemic Subjects

Miettinen¹

1979

J. Clin. Invest.

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A B S T R A C T Effects of neomycin were studied on serum cholesterol and fecal steroids in hypercholesterolemic patients during a short treatment period (4 wk) and a long treatment period (16 mo), using small (1.5 g/d) and large (up to 6 g/d) doses alone and in combination with cholestyramine. In the short-term low-dose study the decrease in serum cholesterol by 21% was associated with a proportionate increase in fecal cholesterol elimination as neutral sterols through impaired cholesterol absorption. Serum cholesterol remained low and fecal steroid excretion remained elevated in the long-term neomycin study. Increasing the dosage from 1.5 to 6 g/d at the end of the 16-mo period brought about a further slight decrease in serum cholesterol and a small further increase in fecal neutral and acidic steroids. The increases in fecal bile acids and fat but not in neutral sterols were positively correlated with the increases in the neomycin dosage. Thus, large neomycin doses can also cause bile acid malabsorption. In another series of patients, a decrease (25%) in serum cholesterol by cholestyramine was associated with a proportional increase in the fecal elimination of cholesterol (2.5-fold) as bile acids. The inclusion of neomycin in cholestyramine therapy further increased fecal steroid output (solely as neutral sterols) by only about one-fifth ofthat due to cholestyramine, but further decreased serum cholesterol almost to the same extent (-17%) as cholestyramine alone. The overall decrease was 38%, no side effects occurred, and the patients found combination therapy convenient. Neomycin decreased serum cholesterol in

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The mechanisms of and the interrelationship between bile acid and chylomicron-mediated regulation of hepatic cholesterol synthesis in the liver of the rat.

Cited by 58 publications

References 50 publications

Comparative effects of cholestanol and cholesterol on hepatic sterol and bile acid metabolism in the rat.

Comparative effects of cholestanol and cholesterol on hepatic sterol and bile acid metabolism in the rat.

Effect of β-muricholic acid on the prevention and dissolution of cholesterol gallstones in C57L/J mice

Effects of Neomycin Alone and in Combination with Cholestyramine on Serum Cholesterol and Fecal Steroids in Hypercholesterolemic Subjects

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