scholarly journals Colchicine inhibits hepatic cholesterol synthesis and microsomal 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA reductase) activity

FEBS Letters ◽  
1976 ◽  
Vol 64 (2) ◽  
pp. 346-349 ◽  
Author(s):  
Faith D. Ottery ◽  
Stanley Goldfarb
Keyword(s):  
Cholesterol Synthesis ◽  
Coenzyme A ◽  
Reductase Activity ◽  
Hepatic Cholesterol ◽  
Hmg Coa Reductase ◽  
Hepatic Cholesterol Synthesis ◽  
Coa Reductase

Effect of glucose or fructose feeding on cholesterol synthesis in diabetic animals

1985 ◽  
Vol 249 (5) ◽  
pp. G634-G641 ◽  
Author(s):  
K. R. Feingold ◽  
A. H. Moser
Keyword(s):  
Cholesterol Synthesis ◽  
Reductase Activity ◽  
Active Form ◽  
Diabetic Rats ◽  
Hepatic Cholesterol ◽  
Hmg Coa Reductase ◽  
Hepatic Cholesterol Synthesis ◽  
Streptozotocin Induced Diabetes ◽  
Intestinal Hypertrophy ◽  
Coa Reductase

Previous studies have demonstrated that cholesterol synthesis is increased twofold in the small intestines of rats with streptozotocin-induced diabetes. The purpose of the present study was to determine the effect of adding glucose or fructose to standard rat chow on cholesterol synthesis in control and diabetic rats. In control rats a 25% glucose or fructose diet fed for 21 days markedly inhibited hepatic cholesterol synthesis in the liver. In contrast, in diabetic animals only fructose inhibited hepatic cholesterol synthesis. In both control and diabetic animals the addition of these simple sugars to the diet did not markedly alter extrahepatic cholesterol synthesis. The enhancement of small intestinal cholesterol synthesis observed in diabetic animals was present regardless of the dietary manipulations. Further studies demonstrated that the addition of smaller concentrations of fructose (10%) to standard rat chow decreased hepatic cholesterol synthesis in both control and diabetic rats. Similarly the addition of fructose to the diet of control and diabetics for a period as short as 2 days was also sufficient to inhibit hepatic cholesterol synthesis. In both control and diabetic animals, fructose feeding decreased hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity but did not alter the percentage of HMG-CoA reductase in the active form. Finally, the intestinal hypertrophy and stimulation of intestinal cholesterogenesis that are characteristic of streptozotocin-induced diabetes occurred when either glucose or fructose was the sole caloric source.

Increase in serum and bile cholesterol and HMG-CoA reductase by lovastatin in rats

1991 ◽  
Vol 260 (4) ◽  
pp. G625-G630 ◽  
Author(s):  
S. Yamauchi ◽  
W. G. Linscheer ◽  
D. H. Beach
Keyword(s):  
Cholesterol Synthesis ◽  
Reductase Activity ◽  
Blood Cholesterol ◽  
Biliary Lipid ◽  
Hepatic Cholesterol ◽  
Biliary Cholesterol ◽  
Hmg Coa Reductase ◽  
Hepatic Cholesterol Synthesis ◽  
Microsomal Membranes ◽  
Coa Reductase

Lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, is effective in the treatment of hypercholesterolemic patients and is currently being evaluated as a potential agent for dissolving gallstones. We therefore evaluated its effect on cholesterol metabolism in a rat model. A low-cholesterol diet containing 0.1% lovastatin was fed 15 h and 7 and 21 days. Microsomal HMG-CoA reductase activity, hepatic cholesterol synthesis, blood cholesterol, and biliary lipid output were determined and compared with control rats. Hepatic cholesterol synthesis increased ninefold after 7 days and levels of HMG-CoA reductase activity sevenfold. Biliary cholesterol excretion maximally increased fourfold. Biliary lipid output was still elevated after 21 days of treatment (cholesterol 3-fold and phospholipid 2-fold, P less than 0.01). Bile salt output did not change. Augmented responses to lovastatin were present but less on the high-cholesterol diet. The data are consistent with the hypothesis that lovastatin increases HMG-CoA reductase activity through a feedback mechanism that promoted increased cholesterol synthesis, biliary lipid secretion, and elevated blood cholesterol. There was an apparent coupling of biliary cholesterol output with phospholipids but not with bile salts. Although lovastatin also increased microsomal HMG-CoA reductase activity in humans, cholesterol synthesis is not stimulated but is inhibited. This may be explained by higher permeability of the microsomal membranes for lovastatin. Thus the effect of HMG-CoA reductase inhibitors on cholesterol synthesis in different species should then depend on the properties of microsomal membranes.

Hepatic cholesterol synthesis and esterification in rats after chronic ethanol feeding

1988 ◽  
Vol 74 (4) ◽  
pp. 407-412 ◽  
Author(s):  
S. Venkatesan ◽  
K. J. Simpson ◽  
T. J. Peters
Keyword(s):  
Cholesterol Synthesis ◽  
Reductase Activity ◽  
Cholesterol Acyltransferase ◽  
Sterol Synthesis ◽  
Liver Protein ◽  
Hepatic Cholesterol ◽  
Hepatic Cholesterol Synthesis ◽  
Ethanol Feeding ◽  
Coa Reductase

1. Chronic (5 weeks) alcohol-fed and isocaloric glucose pair-fed control rats had similar body weights, liver weights and liver protein contents. 2. Hepatic esterified cholesterol and triacylglycerol levels were two- to three-fold higher in alcohol-fed rats than in controls. 3. Hepatic cholesterol synthesis rates measured in vivo with 3H2O were significantly reduced in alcohol-fed rats. 4. Hepatic 3-hydroxy-3-methylglutaryl-CoA reductase (NADPH) (EC 1.1.1.34) activity was increased and the apparent Km for 3-hydroxymethyl-3-glutaryl-CoA was decreased in alcohol-fed rats. 5. Hepatic acyl-CoA:cholesterol acyltransferase (cholesterol acyltransferase; EC 2.3.1.26) activity was significantly increased in alcohol-fed rats. 6. These results indicate that there is no direct relationship between 3-hydroxy-3-methylglutaryl-CoA reductase activity and sterol synthesis in liver of alcohol-fed rats.

scholarly journals The absolute rate of cholesterol biosynthesis in monocyte-macrophages from normal and familial hypercholesterolaemic subjects

1984 ◽  
Vol 219 (2) ◽  
pp. 461-470 ◽  
Author(s):  
D D Patel ◽  
C R Pullinger ◽  
B L Knight
Keyword(s):  
Cholesterol Synthesis ◽  
Reductase Activity ◽  
Cholesterol Biosynthesis ◽  
Specific Radioactivity ◽  
Density Lipoprotein ◽  
Cellular Protein ◽  
True Rate ◽  
Hmg Coa Reductase ◽  
Coa Reductase ◽  
In Cells

The true rate of cholesterogenesis in cultured monocyte-macrophages was determined from the incorporation of [2-14C]acetate into cholesterol, using the desmosterol (cholesta-5,24-dien-3 beta-ol) that accumulated in the presence of the drug triparanol to estimate the specific radioactivity of the newly formed sterols. It was shown that this procedure could be successfully adapted for use with cultured monocytes despite the accumulation of other unidentified biosynthetic intermediates. In cells maintained in 20% (v/v) whole serum approx. 25% of the sterol carbon was derived from exogenous acetate. Cholesterol synthesis was as high in normal cells as in cells from homozygous familial hypercholesterolaemic (FH) subjects and accounted for 50% of the increase in cellular cholesterol. The addition of extra low-density lipoprotein (LDL) reduced cholesterol synthesis, apparently through a decrease in the activity of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase). When incubated in lipoprotein-deficient serum some cells did not survive, but those that remained showed a normal increase in protein content; the amount of cellular protein and cholesterol in each well did not increase and cholesterol synthesis was reduced by over 80%. HMG-CoA reductase activity fell less dramatically and the proportion of sterol carbon derived from exogenous acetate increased, suggesting that the low rate of cholesterogenesis with lipoprotein-deficient serum was due to a shortage of substrate. The results indicate that under normal conditions monocyte-macrophages obtain cholesterol from endogenous synthesis rather than through receptor-mediated uptake of LDL, and that synthesis together with non-saturable uptake of LDL provides the majority of the cholesterol required to support growth.

High plasma cholesterol in drug-induced cholestasis is associated with enhanced hepatic cholesterol synthesis

1999 ◽  
Vol 276 (5) ◽  
pp. G1165-G1173 ◽  
Author(s):  
Jeffrey W. Chisholm ◽  
Patrick Nation ◽  
Peter J. Dolphin ◽  
Luis B. Agellon
Keyword(s):  
Bile Acids ◽  
Cholesterol Synthesis ◽  
Cell Membranes ◽  
Reductase Activity ◽  
Plasma Cholesterol ◽  
Hepatic Cell ◽  
Plasma Lipoproteins ◽  
Liver Cholesterol ◽  
Hepatic Cholesterol ◽  
Hepatic Cholesterol Synthesis

In α-naphthylisothiocyanate-treated mice, plasma phospholipid (PL) levels were elevated 10- and 13-fold at 48 and 168 h, respectively, whereas free cholesterol (FC) levels increased between 48 h (17-fold) and 168 h (39-fold). Nearly all of these lipids were localized to lipoprotein X-like particles in the low-density lipoprotein density range. The PL fatty acyl composition was indicative of biliary origin. Liver cholesterol and PL content were near normal at all time points. Hepatic hydroxymethylglutaryl CoA reductase activity was increased sixfold at 48 h, and cholesterol 7α-hydroxylase activity was decreased by ∼70% between 24 and 72 h. These findings suggest a metabolic basis for the appearance of abnormal plasma lipoproteins during cholestasis. Initially, PL and bile acids appear in plasma where they serve to promote the efflux of cholesterol from hepatic cell membranes. Hepatic cholesterol synthesis is then likely stimulated in the response to the depletion of hepatic cell membranes of cholesterol. We speculate that the enhanced synthesis of cholesterol and impaired conversion to bile acids, particularly during the early phase of drug response, contribute to the accumulation of FC in the plasma.

scholarly journals Inhibition of hydroxymethylglutaryl coenzyme A reductase activity induces a paradoxical increase in DNA synthesis in myeloid leukemia cells

Blood ◽  
1991 ◽  
Vol 77 (5) ◽  
pp. 1064-1070 ◽  
Author(s):  
RJ Hohl ◽  
RA Larson ◽  
V Mannickarottu ◽  
S Yachnin
Keyword(s):  
Dna Synthesis ◽  
Myeloid Leukemia ◽  
Coenzyme A ◽  
Reductase Activity ◽  
Myelogenous Leukemia ◽  
Leukemia Cells ◽  
Hmg Coa Reductase ◽  
Cellular Dna ◽  
Coa Reductase ◽  
Inhibition Of Dna Synthesis

Abstract The effects of competitive inhibition of hydroxymethylglutaryl coenzyme A (HMG CoA) reductase by compactin on the in vitro proliferation of peripheral blood myeloid leukemia cells were studied using the cells from 45 patients with acute myeloid leukemia or chronic myelogenous leukemia in blast phase. The cells from 58% of these patients showed a dose-related inhibition of DNA synthesis when incubated with compactin. Unexpectedly, cells from 18% of the patients were resistant to the inhibitory effects of compactin on DNA synthesis and responded to the HMG CoA reductase inhibition with an actual increase in the incorporation of 14C-labeled thymidine into DNA. Another 18% of the patients studied displayed both inhibition and stimulation of DNA synthesis in a biphasic response depending on the particular concentration of compactin used. The maximum enhanced rates of cellular DNA synthesis were observed with lower compactin concentrations (5 x 10(-7) mol/L) than were required for maximum inhibition of DNA synthesis (10(-5) mol/L). Leukemia cells displaying a stimulated response to compactin had a significantly lower baseline DNA synthetic rate than did cells that showed an inhibitory response of DNA synthesis to compactin. There was no correlation between these cells' varying DNA synthetic response to compactin and measures of baseline HMG CoA reductase activity or acetate conversion to cholesterol. Whereas the observation of cellular DNA synthesis stimulation by HMG CoA reductase inhibition has not been observed in other mammalian cells and seems paradoxical, explanations may emerge in light of our growing knowledge concerning the importance of isoprenylation for the function of certain cell regulatory proteins.

Sign in / Sign up

Export Citation Format

Share Document