Factors affecting the diurnal variation in the level of β-hydroxy-β-methylglutaryl coenzyme A reductase and cholesterol-synthesizing activity in rat liver

Dugan, Richard E.; Slakey, Linda L.; Briedis, Anita V.; Porter, John W.

doi:10.1016/0003-9861(72)90188-9

Cited by 113 publications

(34 citation statements)

References 19 publications

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“…Indeed, changes in HMG-CoA reductase activity accurately reflect changes in the rate of cholesterol synthesis (3,4). Interestingly, the activity of the reductase undergoes daily changes of as much as 10-fold (5)(6)(7)(8). The normal diurnal rise in reductase activity has been shown to be due to an increase in the rate of enzyme synthesis (9).…”

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confidence: 99%

Stimulation of Hepatic β-Hydroxy-β-methylglutaryl Coenzyme A Reductase Activity in Hypophysectomized Rats by L-Triiodothyronine

Ness

Dugan

Lakshmanan

et al. 1973

Proc. Natl. Acad. Sci. U.S.A.

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Diurnally varying activity of hepatic jB-hydroxy-fl-methylglutaryl coenzyme A reductase (EC 1.1.1.34) was decreased to very low levels in hypophysectomized rats with no discernable diurnal rhythm retained. Administration of triiodothyronine (100 jg/100 g of body weight) produced a supranormal level of reductase activity, about 3-4 times the highest activity found in normal rats. 0-Hydroxy-#-methylglutaryl coenzyme A (HMG-CoA) reductase (EC 1.1.1.34) catalyzes the reduction of HMG-CoA to mevalonate, which is the first committed step in the pathway of cholesterol biosynthesis. This reaction has been established as rate-limiting in the over-all conversion of acetate to cholesterol (1, 2). Indeed, changes in HMG-CoA reductase activity accurately reflect changes in the rate of cholesterol synthesis (3, 4). Interestingly, the activity of the reductase undergoes daily changes of as much as 10-fold (5-8). The normal diurnal rise in reductase activity has been shown to be due to an increase in the rate of enzyme synthesis (9). Recently, we have shown (10) that the activity of HMGCoA reductase was stimulated markedly by insulin treatment. We have further demonstrated that reductase activity was reduced to low levels in diabetic rats with only a negligible diurnal rhythm present seven days after the onset of diabetes (11). Administration of insulin restored the activity to nearly normal levels within 2 hr. Other hormones that have been implicated in stimulating cholesterol biosynthesis are thyroid hormones (12, 13) and norepinephrine (14). Guder et al. (13) have shown that hepatic HMG-CoA reductase activity was decreased to less than 50% of normal in hypothyroid rats (produced by 13l1 treatment). A single injection of triiodothyronine (T3) to these hypothyroid rats restored the activity to that of normal animals within 48 hr. In hypophysectomized rats, hepatic cholesterogenesis was reduced to even lower levels (15) than in hypothyroid rats.In this communication we demonstrate that hepatic HMGCoA reductase activity is markedly lowered in hypophysectomized rats with no detectable diurnal rhythm present. Administration of T3 to these animals increases reductase activity to a supranormal level (3-4 times the highest level found in normal rats). MATERIALS AND METHODS Materials. iTriiodothyronine (T3) and [3-14C]0-hydroxy-,-methylglutaric acid were purchased from Sigma Chemical and New England Nuclear Corp., respectively. Other chemicals were of reagent grade.[s-'4C ]b-Hydroxy-g-methylglutaric acid was converted to the anhydride by the dicyclohexylcarbodiimide method of Goldfarb and Pitot (16). The coenzyme A ester was prepared from the anhydride as described by Hilz et al. (17) and then purified by descending paper chromatography on Whatman 3 MM with isobutyric acid-concentrated ammonia-0.1 M EDTA (pH 4.5)-H20 (124:5:2:75) as the solvent system. Treatment of Animals. Young adult male albino rats weighing 140-160 g were purchased from Holtzman. Animals were hypophysectomized by Altech Laboratories of Madison, Wisc. The h...

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confidence: 99%

Stimulation of Hepatic β-Hydroxy-β-methylglutaryl Coenzyme A Reductase Activity in Hypophysectomized Rats by L-Triiodothyronine

Ness

Dugan

Lakshmanan

et al. 1973

Proc. Natl. Acad. Sci. U.S.A.

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“…Experiments are in progress to prove this hypothesis. The conservation of the rhythm in fasted rats [4] shows that food intake does not generate the rhythm. However, cyclic availability of food can act as a synchronizer of the rhythm [4] that overrides the "Zeitgeber" effect of the light-dark cycle [ 181.…”

Section: Influence Ofganglionectomymentioning

confidence: 98%

“…If rats have access to food only for a brief fraction of the light period, the maximum of activity of HMGCoA reductase is found in the light period [4]. The rhythm is maintained even when the animals did not have access to food during the last feeding period scheduled [4]. Similarly, the rhythm of the enzyme persists with rats fasted for 24 hr, albeit with a strongly reduced amplitude [2].…”

Section: Introductionmentioning

confidence: 99%

“…rats eat much more during the dark period than during the light period [6]. If rats have access to food only for a brief fraction of the light period, the maximum of activity of HMGCoA reductase is found in the light period [4]. The rhythm is maintained even when the animals did not have access to food during the last feeding period scheduled [4].…”

Section: Introductionmentioning

confidence: 99%

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The influence of bilateral superior cervical ganglionectomy, continuous light and continuous darkness on the diurnal rhythm of hydroxymethylglutaryl‐coenzyme a reductase in rat liver

Huber

Latzin

Langguth³

et al. 1973

FEBS Letters

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“…Therefore, the committed step iu cholesterol biosynthesis may exist prior to that catalyzed by HMG-CoA reductase (Fig ure 1, Derapsey, 1974 (Sugiyama et alj 1972). Dugan et al (1972) have evidence that the diurnal alteration In choles terol biosynthesis is controlled by an enzyme prior to HMG-CoA reductase.…”

Section: Control Mechanismsmentioning

confidence: 99%

Influence of meal pattern and dietary fat on cholesterol metabolism in adult rats recovering from undernutrition

Carlson

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Factors affecting the diurnal variation in the level of β-hydroxy-β-methylglutaryl coenzyme A reductase and cholesterol-synthesizing activity in rat liver

Cited by 113 publications

References 19 publications

Stimulation of Hepatic β-Hydroxy-β-methylglutaryl Coenzyme A Reductase Activity in Hypophysectomized Rats by L-Triiodothyronine

Stimulation of Hepatic β-Hydroxy-β-methylglutaryl Coenzyme A Reductase Activity in Hypophysectomized Rats by L-Triiodothyronine

The influence of bilateral superior cervical ganglionectomy, continuous light and continuous darkness on the diurnal rhythm of hydroxymethylglutaryl‐coenzyme a reductase in rat liver

Influence of meal pattern and dietary fat on cholesterol metabolism in adult rats recovering from undernutrition

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