Regulation of cholesterol synthesis in the liver and mammary gland of the lactating rat

Gibbons, Geoffrey F.; Pullinger, Clive R.; Munday, Michael R.; Williamson, Dermot H.

doi:10.1042/bj2120843

Cited by 45 publications

(39 citation statements)

References 21 publications

(14 reference statements)

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“…A 55 % decrease in the rate of lipid synthesis was observed in the liver. This approximates to the decline in hepatic lipogenesis which has been observed in response to 6 h starvation in lactating rates (Gibbons et al, 1983;reviewed by Williamson et at., 1983) and closely correlates with the 69 % decrease in hepatic PDHa activity (Table 1). Starvation for a more prolonged period (48 h) further decreased rates of hepatic lipogenesis, to approx.…”

Section: Methodsmentioning

confidence: 99%

Pyruvate dehydrogenase activities and rates of lipogenesis during the fed-to-starved transition in liver and brown adipose tissue of the rat

Holness

Sugden

1990

Biochemical Journal

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The percentages of pyruvate dehydrogenase complex (PDH) in the active form (PDHa) in two lipogenic tissues (liver and brown adipose tissue) in the fed state were 12.00% and 13.40% respectively. After acute (0.5 h) insulin treatment, PDHa activities had increased by 77 % in liver and by 234 % in brown fat. Significant decreases in PDHa activities were observed in both tissues by 5 h after the removal of food. The patterns of decline in PDHa activities in the two lipogenic tissues were similar in that the major decreases in activities were observed within the first 7 h of starvation. The significant decreases in PDHa activities observed after starvation for 6 h were accompanied by decreased rates of lipogenesis. Hepatic and brown-fat PDHa activities after acute (30 min) exposure to exogenous insulin were less in 6 h-starved than in fed rats, but the absolute increases in PDHa activities over the 30 min exposure period were similar in fed and 6 h-starved rats. Increases in PDHa activities were paralleled by increases in lipid synthesis in both tissues. Re-activation of PDH in response to insulin treatment or chow re-feeding after 48 h starvation occurred more rapidly in brown adipose tissue than in liver. The results are discussed in relation to the importance of the activity of the PDH complex as a determinant of the total rate of lipogenesis during the fed-to-starved transition and after insulin challenge or re-feeding.

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Section: Methodsmentioning

confidence: 99%

Pyruvate dehydrogenase activities and rates of lipogenesis during the fed-to-starved transition in liver and brown adipose tissue of the rat

Holness

Sugden

1990

Biochemical Journal

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“…This mechanism may explain how n-3 PUFA lower serum cholesterol and decrease HMG-CoA reductase. The mammary gland, however, is capable of synthesizing cholesterol for secretion during lactation and may be subject to unique regulatory mechanisms (19).…”

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confidence: 99%

Regulation of mevalonate synthesis in low density lipoprotein receptor knockout mice fed n‐3 or n‐6 polyunsaturated fatty acids

El-Sohemy

Archer

1999

Lipids

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3-Hydroxy-3-methylglutaryl (HMG)-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis, catalyzes the formation of mevalonate which is also required for cell proliferation. Changes in HMG-CoA reductase may mediate the differential effects of n-3 and n-6 polyunsaturated fatty acids (PUFA) on experimental mammary tumorigenesis, but the mechanisms by which these fatty acids regulate HMG-CoA reductase are unclear. To determine whether the low density lipoprotein receptor (LDL-R) is required for this regulation, groups of female LDL-R knockout (-/-) and wild-type (+/+) mice were fed 7% fat diets rich in either n-3 (menhaden oil) or n-6 (safflower oil) PUFA for 1 wk. Dietary PUFA and deletion of the LDL-R had independent effects on HMG-CoA reductase and serum lipids, and a significant diet-gene interaction was observed. The effects of PUFA on HMG-CoA reductase in the mammary gland, but not the liver, were mediated by the LDL-R. We also observed that differences in HMG-CoA reductase and serum LDL-cholesterol, high density lipoprotein cholesterol, and triglycerides between -/- and +/+ mice were dependent on whether the mice were fed n-3 or n-6 PUFA. Differences between -/- and +/+ mice were much greater when animals were fed n-6 PUFA rather than n-3 PUFA. These results show that the LDL-R mediates the effects of PUFA on HMG-CoA reductase in the mammary gland but not the liver. Furthermore, the composition of dietary PUFA profoundly influences the effects of deleting the LDL-R on HMG-CoA reductase and serum lipids and suggests that diet may influence the phenotype of other knock-out or transgenic animals.

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“…Finally, the rates of hepatic cholesterol synthesis (Edwards et al, 1972;Rodwell et al, 1976;Gibbons et al, 1983) and lipogenesis (Scott & Potter, 1970;Hems et al, 1975;) vary with a diurnal periodicity which appears to be dependent on the changing pattern of food intake. Previous work has shown that the magnitude of the lipogenic response to insulin, glucagon and lipogenic precursors in vitro is dependent on the time of day at which the hepatocytes were prepared (Gibbons et al, 1984).…”

Section: Introductionmentioning

confidence: 99%

Diurnal variations in the effects of an unsaturated-fat-containing diet on fatty acid and cholesterol synthesis in rat hepatocytes

Gibbons¹,

Pullinger²

1986

Biochemical Journal

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1. Rats were fed ad libitum on either a standard high-carbohydrate diet, or a standard diet supplemented with 15 % corn oil. Hepatocytes were prepared either during the light phase (L2-hepatocytes) or during the dark phase (D6-hepatocytes) of the diurnal cycle. 2. In hepatocytes from rats fed on the fat-containing diet, fatty acid synthesis (lipogenesis) was suppressed to a much greater extent at D, than at L2. The magnitude of the increase in plasma-free fatty acid concentration was similar at the two times of day. 3. The rate of cholesterol synthesis was also significantly suppressed in the D6,-but not in the L2-hepatocytes. This differential inhibition resulted in the abolition of the normal diurnal rhythm of cholesterogenesis. The initial activity of 3-hydroxy-3-methylglutaryl-CoA reductase in hepatocytes was also suppressed by corn-oil feeding at D6, but not at L2. 4. In D,-hepatocytes, the inhibitory effect of the high-fat diet on the conversion of lactate into cholesterol and fatty acids was greater than that on total carbon flux into these substances for all endogenous sources. Despite this, under these conditions a high concentration of lactate and pyruvate resulted in a several-fold stimulation of total carbon flux into fatty acids. 5. In hepatocytes prepared at L2, fat-feeding had little effect on the degree of stimulation of lipogenesis by insulin or inhibition by glucagon.

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Regulation of cholesterol synthesis in the liver and mammary gland of the lactating rat

Cited by 45 publications

References 21 publications

Pyruvate dehydrogenase activities and rates of lipogenesis during the fed-to-starved transition in liver and brown adipose tissue of the rat

Pyruvate dehydrogenase activities and rates of lipogenesis during the fed-to-starved transition in liver and brown adipose tissue of the rat

Regulation of mevalonate synthesis in low density lipoprotein receptor knockout mice fed n‐3 or n‐6 polyunsaturated fatty acids

Diurnal variations in the effects of an unsaturated-fat-containing diet on fatty acid and cholesterol synthesis in rat hepatocytes

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