Fatty acyl-CoA inhibition of β-hydroxy-β-methylglutaryl-CoA reductase activity

Faas, Fred H.; Carter, William J.; Wynn, James

doi:10.1016/0005-2760(78)90139-x

Cited by 15 publications

(5 citation statements)

References 8 publications

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“…As in rats [10], increasing dietary pectin increased HMGR activity. Diets high in linoleate resulted in greater HMGR activity than diets with high saturated fat as reported for rats [4], The results are analogous to reported effects in rats of such diets on cholesterol synthesis from acetate [11]. A decline in cholesterol synthesis with maturation has also been re ported in rats [12], Few observations have been made of old rats, but there may be a decrease in cholesterol synthesis after the age of 18 months [13].…”

Section: Discussionsupporting

confidence: 75%

“…Energy metabolism is also an effector of cholesterol metabolism regulation [5], but studies of cholesterol metabolism in relation to energy usage have not been included in characterization of differences between geHydroxymethylglutaryl coenzyme A re ductase (HMGR, EC 1.1.1.34) activity is well known to vary with age [1], sex [2], and diurnal cycle [1,2], Many factors in the diet, including plant fiber [3] and type of fat [4], also act to influence HMGR activity. These results have been observed with rats as well as with some other species.…”

Section: Introductionmentioning

confidence: 99%

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Hepatic Hydroxymethylglutaryl Coenzyme A Reductase Activity in Inbred Strains of Mice

Dupont¹,

Aubert²,

Kuan³

et al. 1988

Enzyme

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Hydroxymethylglutaryl coenzyme A reductase (HMGR) activity is a major factor in the regulation of cholesterol homeostasis. Enzyme activity is known to vary with age, sex, diurnal cycle, and dietary properties in rats. Mice are available in numerous genetic strains and could be a useful inexpensive animal model for studying diet and genetic interactions in the regulation of cholesterol metabolism. Obese and non-obese C57BL/6J, CBA/J, and obese and non-obese DW db^Pas mice were subjected to variations in light cycle, feeding schedule, and pectin and fat composition of their diets. They were then killed by decapitation, and hepatic microsomal HMGR analyzed. The mice responded in the same ways as rats to light cycle, feeding pattern, and sex difference. They exhibited marked differences in HMGR activity due to age, genotype, strain, and diet variations. We conclude that mice will, indeed, offer an excellent animal model for the study of cholesterol metabolism regulation.

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Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Hepatic Hydroxymethylglutaryl Coenzyme A Reductase Activity in Inbred Strains of Mice

Dupont¹,

Aubert²,

Kuan³

et al. 1988

Enzyme

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“…We focused on HMGCoA reductase for two reasons. First, reductase activity is directly inhibited by CoA thioesters (40,56,57); second, the hypolipidemic compound S-2E is converted to a CoA derivative and S-2E-CoA directly inhibits HMG-CoA reductase in a cell-free assay (58). However, we found that ESP 55016-CoA did not inhibit reductase in a cell-free assay under a variety of conditions.…”

Section: Discussionmentioning

confidence: 67%

Effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndrome

Cramer¹,

Goetz²,

Hopson

et al. 2004

Journal of Lipid Research

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We have identified a novel -hydroxy-alkanedicarboxylic acid, ESP 55016, that favorably alters serum lipid variables in obese female Zucker (fa/fa) rats. ESP 55016 reduced serum non-HDL-cholesterol (non-HDL-C), triglyceride, and nonesterified fatty acid levels while increasing serum HDL-C and ␤ -hydroxybutyrate levels in a dose-dependent manner. ESP 55016 reduced fasting serum insulin and glucose levels while also suppressing weight gain. In primary rat hepatocytes, ESP 55016 increased the oxidation of

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“…In addition, intrahepatic fatty acyl-CoAs increase during fasting (Tubbs and Garland, 1964), and Hmgcr is inhibited by select fatty acyl-CoAs in vitro (Kuroda and Endo, 1976; Faas et al, 1977; Faas et al, 1978; Lehrer et al, 1981; Roitelman and Shechter, 1989). Detailed kinetic analyses, however, were not reported in some of these studies and, for short-chain fatty acyl-CoAs, the kinetic parameters do not support physiological inhibition.…”

Section: Resultsmentioning

confidence: 99%

Polyunsaturated fatty acyl-coenzyme As are inhibitors of cholesterol biosynthesis in zebrafish and mice

Karanth

Tran

Kuberan

et al. 2013

Disease Models &Amp; Mechanisms

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SUMMARYLipid disorders pose therapeutic challenges. Previously we discovered that mutation of the hepatocyte β-hydroxybutyrate transporter Slc16a6a in zebrafish causes hepatic steatosis during fasting, marked by increased hepatic triacylglycerol, but not cholesterol. This selective diversion of trapped ketogenic carbon atoms is surprising because acetate and acetoacetate can exit mitochondria and can be incorporated into both fatty acids and cholesterol in normal hepatocytes. To elucidate the mechanism of this selective diversion of carbon atoms to fatty acids, we fed wild-type and slc16a6a mutant animals high-protein ketogenic diets. We find that slc16a6a mutants have decreased activity of the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr), despite increased Hmgcr protein abundance and relative incorporation of mevalonate into cholesterol. These observations suggest the presence of an endogenous Hmgcr inhibitor. We took a candidate approach to identify such inhibitors. First, we found that mutant livers accumulate multiple polyunsaturated fatty acids (PUFAs) and PUFA-CoAs, and we showed that human HMGCR is inhibited by PUFA-CoAs in vitro. Second, we injected mice with an ethyl ester of the PUFA eicosapentaenoic acid and observed an acute decrease in hepatic Hmgcr activity, without alteration in Hmgcr protein abundance. These results elucidate a mechanism for PUFA-mediated cholesterol lowering through direct inhibition of Hmgcr.

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Fatty acyl-CoA inhibition of β-hydroxy-β-methylglutaryl-CoA reductase activity

Cited by 15 publications

References 8 publications

Hepatic Hydroxymethylglutaryl Coenzyme A Reductase Activity in Inbred Strains of Mice

Hepatic Hydroxymethylglutaryl Coenzyme A Reductase Activity in Inbred Strains of Mice

Effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndrome

Polyunsaturated fatty acyl-coenzyme As are inhibitors of cholesterol biosynthesis in zebrafish and mice

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