Cholesterol synthesis in vivo and in vitro in the WHHL rabbit, an animal with defective low density lipoprotein receptors

J. M. Dietschy, T. Kita, K. E. Suckling, J. L. Goldstein, M. S. Brown

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Abstract

These studies were undertaken to measure rates of synthesis of digitonin-precipitable sterols in vivo and in vitro in control rabbits (New Zealand (NZ) control) and in homozygous Watanabe heritable hyperlipidemic rabbits (WHHL) that lack receptors for low density lipoproteins (LDL). The plasma cholesterol concentration in NZ control fetuses equaled 79 mg/dl, rose to 315 mg/dl 12 days after birth, and fell to 80 mg/dl in young adult animals. At these same ages, cholesterol concentrations in the WHH animals equal 315, 625, and 715 mg/dl, respectively. The rate of whole animal sterol synthesis in vivo, expressed as the μmol of [3H]water incorporated into sterols per hr per kg of body weight, was lower in the WHHL animals than in the NZ controls both in the fetuses (108 vs 176) and in the adult animals (48 vs 66). In adult NZ controls the content of newly synthesized sterols (rate of sterol synthesis) per g of tissue was highest in the liver (538 nmol/g per hr), adrenal gland (438), small bowel (371), and ovary (225) while lower rates of synthesis were found in 15 other tissues. In the WHHL rabbits a higher content of [3H]sterols was found only in the adrenal gland (2,215) while synthesis was suppressed in the liver (310), colon, lung, and kidney, and was unchanged in the remaining organs. These findings were confirmed by measurements of rates of sterol synthesis in the same tissues in vitro. When whole organ weight was taken into consideration, the tissues that were the major contributors to whole body sterols synthesis in both types of rabbits were liver, small bowel, skin, and carcass. However, it was the lower rate of synthesis in the liver of the WHHL animals that alone accounted for the lower rate of whole animal sterol synthesis seen in these rabbits. These studies demonstrate that in WHHL animals that lack LDL receptors and that have very high levels of circulating LDL cholesterol, the rate of cholesterol synthesis in nearly all tissues is normal but in the liver is significantly suppressed. Only the adrenal gland manifested enhanced synthesis. Such findings suggest that in the WHHL rabbit where LDL receptor activity is reduced and plasma LDL levels rise, mechanisms other than receptor-mediated LDL uptake may act to deliver cholesterol to the cells of the various organs and to the liver.

Original languageEnglish (US)
Pages (from-to)469-480
Number of pages12
JournalJournal of Lipid Research
Volume24
Issue number4
StatePublished - 1983

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LDL Receptors
Sterols
Animals
Cholesterol
Rabbits
Liver
Tissue
Adrenal Glands
New Zealand
LDL Lipoproteins
Fetus
In Vitro Techniques
Plasmas
Digitonin
Organ Size
LDL Cholesterol
Young Adult
Ovary
Skin
Colon

ASJC Scopus subject areas

  • Endocrinology

Cite this

Cholesterol synthesis in vivo and in vitro in the WHHL rabbit, an animal with defective low density lipoprotein receptors. / Dietschy, J. M.; Kita, T.; Suckling, K. E.; Goldstein, J. L.; Brown, M. S.

In: Journal of Lipid Research, Vol. 24, No. 4, 1983, p. 469-480.

Research output: Contribution to journalArticle

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abstract = "These studies were undertaken to measure rates of synthesis of digitonin-precipitable sterols in vivo and in vitro in control rabbits (New Zealand (NZ) control) and in homozygous Watanabe heritable hyperlipidemic rabbits (WHHL) that lack receptors for low density lipoproteins (LDL). The plasma cholesterol concentration in NZ control fetuses equaled 79 mg/dl, rose to 315 mg/dl 12 days after birth, and fell to 80 mg/dl in young adult animals. At these same ages, cholesterol concentrations in the WHH animals equal 315, 625, and 715 mg/dl, respectively. The rate of whole animal sterol synthesis in vivo, expressed as the μmol of [3H]water incorporated into sterols per hr per kg of body weight, was lower in the WHHL animals than in the NZ controls both in the fetuses (108 vs 176) and in the adult animals (48 vs 66). In adult NZ controls the content of newly synthesized sterols (rate of sterol synthesis) per g of tissue was highest in the liver (538 nmol/g per hr), adrenal gland (438), small bowel (371), and ovary (225) while lower rates of synthesis were found in 15 other tissues. In the WHHL rabbits a higher content of [3H]sterols was found only in the adrenal gland (2,215) while synthesis was suppressed in the liver (310), colon, lung, and kidney, and was unchanged in the remaining organs. These findings were confirmed by measurements of rates of sterol synthesis in the same tissues in vitro. When whole organ weight was taken into consideration, the tissues that were the major contributors to whole body sterols synthesis in both types of rabbits were liver, small bowel, skin, and carcass. However, it was the lower rate of synthesis in the liver of the WHHL animals that alone accounted for the lower rate of whole animal sterol synthesis seen in these rabbits. These studies demonstrate that in WHHL animals that lack LDL receptors and that have very high levels of circulating LDL cholesterol, the rate of cholesterol synthesis in nearly all tissues is normal but in the liver is significantly suppressed. Only the adrenal gland manifested enhanced synthesis. Such findings suggest that in the WHHL rabbit where LDL receptor activity is reduced and plasma LDL levels rise, mechanisms other than receptor-mediated LDL uptake may act to deliver cholesterol to the cells of the various organs and to the liver.",
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T1 - Cholesterol synthesis in vivo and in vitro in the WHHL rabbit, an animal with defective low density lipoprotein receptors

AU - Dietschy, J. M.

AU - Kita, T.

AU - Suckling, K. E.

AU - Goldstein, J. L.

AU - Brown, M. S.

PY - 1983

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N2 - These studies were undertaken to measure rates of synthesis of digitonin-precipitable sterols in vivo and in vitro in control rabbits (New Zealand (NZ) control) and in homozygous Watanabe heritable hyperlipidemic rabbits (WHHL) that lack receptors for low density lipoproteins (LDL). The plasma cholesterol concentration in NZ control fetuses equaled 79 mg/dl, rose to 315 mg/dl 12 days after birth, and fell to 80 mg/dl in young adult animals. At these same ages, cholesterol concentrations in the WHH animals equal 315, 625, and 715 mg/dl, respectively. The rate of whole animal sterol synthesis in vivo, expressed as the μmol of [3H]water incorporated into sterols per hr per kg of body weight, was lower in the WHHL animals than in the NZ controls both in the fetuses (108 vs 176) and in the adult animals (48 vs 66). In adult NZ controls the content of newly synthesized sterols (rate of sterol synthesis) per g of tissue was highest in the liver (538 nmol/g per hr), adrenal gland (438), small bowel (371), and ovary (225) while lower rates of synthesis were found in 15 other tissues. In the WHHL rabbits a higher content of [3H]sterols was found only in the adrenal gland (2,215) while synthesis was suppressed in the liver (310), colon, lung, and kidney, and was unchanged in the remaining organs. These findings were confirmed by measurements of rates of sterol synthesis in the same tissues in vitro. When whole organ weight was taken into consideration, the tissues that were the major contributors to whole body sterols synthesis in both types of rabbits were liver, small bowel, skin, and carcass. However, it was the lower rate of synthesis in the liver of the WHHL animals that alone accounted for the lower rate of whole animal sterol synthesis seen in these rabbits. These studies demonstrate that in WHHL animals that lack LDL receptors and that have very high levels of circulating LDL cholesterol, the rate of cholesterol synthesis in nearly all tissues is normal but in the liver is significantly suppressed. Only the adrenal gland manifested enhanced synthesis. Such findings suggest that in the WHHL rabbit where LDL receptor activity is reduced and plasma LDL levels rise, mechanisms other than receptor-mediated LDL uptake may act to deliver cholesterol to the cells of the various organs and to the liver.

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