Dietary carbohydrate decreases 3-hydroxy-3-methylglutaryl coenzyme a reductase activity and cholesterol synthesis in rat liver

Stacpoole, Peter W.; Harwood, H. James; Varnado, Carol E.

doi:10.1016/0006-291x(83)91082-3

Cited by 12 publications

(4 citation statements)

References 17 publications

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“…15 Indeed, there is evidence in rats that increased glucose feeding results in reduced 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity and reduced cholesterol synthesis. 16 - 17 As we discuss below, these effects may explain the difference in apoB response elicited by increased delivery of exogenous fatty acids compared with that observed with increased glucose delivery.…”

Section: Substrate Delivery As a Determinant Of Hepatic Apob Secretionmentioning

confidence: 97%

Substrate delivery as a determinant of hepatic apoB secretion.

Sniderman

Cianflone

1993

Arterioscler Thromb

187

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L ipoprotein levels in plasma are a function of the rate at which they are produced as well as the rate at which they are catabolized. Both processes are critical. Yet the greatest proportion of clinical investigative energy by far has focused on the latter, with relatively little interest, by contrast, in the former. To be sure, considerable work has been done by basic scientists to elucidate the steps involved in the formation and secretion of a hepatic particle (for a general review, see Reference 1). However, for the most part, this knowledge has not yet altered our approach to the classification and therapy of dyslipoproteinemias in humans. This situation stands in marked contrast to the errors of catabolism, in which advances in basic knowledge have been tightly coupled to a better understanding of the pathogenesis of distinct clinical disorders. As a result, among physicians there is a widespread failure to appreciate that not only can hepatocytes vary the composition of the apolipoprotein (apo)B particles that they secrete but even more importantly, that they can also vary the rate at which such particles emerge into the circulation. The purpose of this review is to demonstrate that such differences can be related in large degree to differences in the delivery of various substrates to the liver, and if this is recognized, how our understanding of the pathophysiology of a number of human dyslipoproteinemias can be increased. Effect of Carbohydrate on the Assembly, Secretion,and Plasma Metabolism of VLDL Perhaps because triglycerides are the major lipid component of very low density lipoprotein (VLDL), the general view appears to be that the rate of secretion of such particles is merely a simple and direct function of the corresponding rate of triglyceride synthesis within the hepatocyte. Experimentally, however, this does not appear to be the case. For example, increasing the glucose concentration in the medium surrounding HepG2 cells results in increased intracellular triglyceride synthesis and secretion but does not alter the rate of apoB secretion.2 The effect of glucose under these circumstances, therefore, is to alter the composition of the secreted apoB particles so that they contain more

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Section: Substrate Delivery As a Determinant Of Hepatic Apob Secretionmentioning

confidence: 97%

Substrate delivery as a determinant of hepatic apoB secretion.

Sniderman

Cianflone

1993

Arterioscler Thromb

187

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“…DCA inhibits hepatic triglyceride synthesis (Stacpoole, et al, 1983b). The mechanism for this effect is unknown, but may be due to the ability of the drug to lower tissue levels of citrate (Stacpoole & Felts, 1970), a precursor of cellular lipid synthesis.…”

Section: Therapeutic Uses Of Dcamentioning

confidence: 99%

Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1

James

Jahn

Zhong

et al. 2017

Pharmacology & Therapeutics

Self Cite

110

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Dichloroacetate (DCA) has several therapeutic applications based on its pharmacological property of inhibiting pyruvate dehydrogenase kinase. DCA has been used to treat inherited mitochondrial disorders that result in lactic acidosis, as well as pulmonary hypertension and several different solid tumors, the latter through its ability to reverse the Warburg effect in cancer cells and restore aerobic glycolysis. The main clinically limiting toxicity is reversible peripheral neuropathy. Although administration of high doses to rodents can result in liver cancer, there is no evidence that DCA is a human carcinogen. In all studied species, including humans, DCA has the interesting property of inhibiting its own metabolism upon repeat dosing, resulting in alteration of its pharmacokinetics. The first step in DCA metabolism is conversion to glyoxylate catalyzed by glutathione transferase zeta 1 (GSTZ1), for which DCA is a mechanism-based inactivator. The rate of GSTZ1 inactivation by DCA is influenced by age, GSTZ1 haplotype and cellular concentrations of chloride. The effect of DCA on its own metabolism complicates the selection of an effective dose with minimal side effects.

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“…The acute effect of glucose infusion on the rate of cholesterol synthesis is unclear, but glucose is known to be a poor substrate for cholesterol synthesis compared with lactate or fatty acids [45]. There is evidence that in rats given diets high in carbohydrate and low in fat for more than 14 days the activity of HMG-CoA reductase in the liver decreases and is paralleled by a fall in hepatic cholesterologenesis and an increase in triglyceride formation [46]. In our study triglycerides decreased significantly during the insulin study in both groups (data not shown) despite the glucose infused, probably as a result of the dramatic fall in NEFAs.…”

Section: Discussionmentioning

confidence: 99%

Acute hyperinsulinaemia decreases cholesterol synthesis less in subjects with non‐insulin‐dependent diabetes mellitus than in non‐diabetic subjects

Naoumova

Cummings

Watts

et al. 1996

Eur J Clin Investigation

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To investigate the effect of insulin on cholesterol synthesis in vivo we measured plasma mevalonic acid (MVA) concentrations using gas chromatography-mass spectrometry in six non-obese patients with non-insulin-dependent diabetes mellitus (NIDDM) [four men, two women; age 57.5 +/- 2.2 years (mean +/- SEM); glycated haemoglobin (HbA1) 8.5 +/- 0.5%; total cholesterol (TC) 5.7 +/- 0.5 mmol L-1, triglyceride (TG) 3.8 +/- 0.9 mmol L-1] and six non-diabetic, sex- and age-matched control subjects (age 55.7 +/- 2.8 years; HbA1 6.5 +/- 0.1%; TC 5.4 +/- 0.3 mmol L-1, TG 1.2 +/- 0.1 mmol L-1). Subjects were studied twice: during 13-h hyperinsulinaemic (1 mu kg-1 min-1), euglycaemic (5 mmol L-1) clamp and during a saline infusion. Baseline MVA concentration was significantly higher in diabetic patients than in control subjects (9.8 +/- 0.7 ng mL-1 vs. 5.6 +/- 0.9 ng mL-1, P = 0.004). At the end of each study, MVA concentration, expressed as a percentage of baseline, was significantly lower during the hyperinsulinaemic, euglycaemic clamp than during the saline study in both the diabetic (54.4 +/- 5.3% vs. 69.6 +/- 6.3%, P = 0.036) and control subjects (30.5 +/- 3.4% vs. 61.7 +/- 6.0%, P = 0.01). However, the decrease in MVA during the hyperinsulinaemic clamp study was more marked in the control subjects than in the diabetic subjects (P = 0.03). A significant positive correlation was found between percentage decrease of MVA and non-esterified fatty acids following the insulin clamp in NIDDM (r = 0.83, P = 0.04). We conclude that acute hyperinsulinaemia decreases cholesterol synthesis less in subjects with NIDDM than in non-diabetic subjects and that this phenomenon, together with increased basal cholesterol synthesis in NIDDM, may in part be due to insulin resistance.

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Dietary carbohydrate decreases 3-hydroxy-3-methylglutaryl coenzyme a reductase activity and cholesterol synthesis in rat liver

Cited by 12 publications

References 17 publications

Substrate delivery as a determinant of hepatic apoB secretion.

Substrate delivery as a determinant of hepatic apoB secretion.

Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1

Acute hyperinsulinaemia decreases cholesterol synthesis less in subjects with non‐insulin‐dependent diabetes mellitus than in non‐diabetic subjects

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