Regulation of Cholesterol Metabolism in the Dog

Pertsemlidis, Demetrius; Kirchman, Ernest H.; Ahrens, E. H.

doi:10.1172/jci107424

Cited by 62 publications

(12 citation statements)

References 13 publications

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“…By using a value of 5 x 10-18 g of cholesterol per particle for chylomicron remnants (5), and based on the above measurements and assumptions, we calculated that the liver could take up -1 g of cholesterol per day via the hepatic apo-E receptors. This value compares favorably with 1-1.5 g/d of absorbed cholesterol delivered to the liver of dogs fed various levels of dietary cholesterol as determined previously in sterol balance studies (27)(28)(29).…”

Section: Resultssupporting

confidence: 75%

Two independent lipoprotein receptors on hepatic membranes of dog, swine, and man. Apo-B,E and apo-E receptors.

Mahley¹,

Hui²,

Innerarity³

et al. 1981

J. Clin. Invest.

373

117

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A B S T R A C T We have reported previously that canine livers possess two distinct lipoprotein receptors, an apoprotein (apo)-B,E receptor capable ofbinding the apo-B-containing low density lipoproteins (LDL) and the apo-E-containing cholesterol-induced high density lipoproteins (HDL,), and an apo-E receptor capable of binding apo-E HDLC but not LDL. Both the apo-B,E and apo-E receptors were found on the liver membranes obtained from immature growing dogs, but only the apo-E receptors were detected on the hepatic membranes of adult dogs.In this study, the expression ofthe apo-B,E receptors, as determined by canine LDL binding to the hepatic membranes, was found to be highly dependent on the age of the dog and decreased linearly with increasing age. Approximately 30 ng of LDL protein per milligram of membrane protein were bound via the apo-B,E receptors to the hepatic membranes of 7-to 8-wk-old immature dogs as compared with no detectable LDL binding in the hepatic membranes of adult dogs (> 1-1.5 yr ofage). Results obtained by in vivo turnover studies of canine 125I-LDL correlated with the in vitro findings. In addition to a decrease in the expression of the hepatic apo-B,E receptors with age, these receptors were regulated, i.e., cholesterol feeding suppressed these receptors in immature dogs and prolonged fasting induced their expression in adult dogs. Previously, it was shown that the apo-B,E receptors were induced in adult livers following treatment with the hypocholesterolemic drug cholestyramine. In striking contrast, the apo-E receptors, as determined by apo-E HDLC bind- ing, remained relatively constant for all ages of dogs studied (10-12 ng/mg). Moreover, the expression of the apo-E receptors was not strictly regulated by the metabolic perturbations that regulated the apo-B,E receptors.Similar results concerning the presence of apo-B,E and apo-E receptors were obtained in swine and in man. The hepatic membranes of adult swine bound only apo-E HDLC (apo-E receptors), whereas the membranes from fetal swine livers bound both LDL and apo-E HDL, (apo-B,E and apo-E receptors). Furthermore, the membranes from adult human liver revealed the presence ofthe apo-E receptors as evidenced by the binding of 12-14 ng of HDL protein per milligram of membrane protein and <1 ng of LDL protein per milligram. The membranes from the human liver also bound human chylomicron remnants and a subfraction of human HDL containing apo-E. These data suggest the importance of the E apoprotein and the apo-E receptors in mediating lipoprotein clearance, including chylomicron remnants, by the liver of adult dogs, swine, and man.

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Section: Resultssupporting

confidence: 75%

Two independent lipoprotein receptors on hepatic membranes of dog, swine, and man. Apo-B,E and apo-E receptors.

Mahley¹,

Hui²,

Innerarity³

et al. 1981

J. Clin. Invest.

373

117

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Section: Ment With Results In Acat2mentioning

confidence: 78%

“…Fourteen years later experiments utilizing complete biliary diversion in dogs fed a cholesterol-free diet provided additional evidence for a non-biliary route of neutral sterol loss (25). This study demonstrated that biliary diversion resulted in complete loss of fecal acidic sterol output, yet fecal neutral sterol output actually increased (25). Based on this observation, the authors speculated "the increased output of fecal neutral steroids could be the result of transfer of plasma cholesterol across the gut wall or due to increased synthesis in the gut."…”

Section: Ment With Results In Acat2mentioning

confidence: 99%

Targeted Depletion of Hepatic ACAT2-driven Cholesterol Esterification Reveals a Non-biliary Route for Fecal Neutral Sterol Loss

Brown

Bell

Alger

et al. 2008

Journal of Biological Chemistry

139

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Deletion of acyl-CoA:cholesterol O-acyltransferase 2 (ACAT2) in mice results in resistance to diet-induced hypercholesterolemia and protection against atherosclerosis. Recently, our group has shown that liver-specific inhibition of ACAT2 via antisense oligonucleotide (ASO)-mediated targeting likewise limits atherosclerosis. However, whether this atheroprotective effect was mediated by: 1) prevention of packaging of cholesterol into apoB-containing lipoproteins, 2) augmentation of nascent HDL cholesterol secretion, or 3) increased hepatobiliary sterol secretion was not examined. Therefore, the purpose of these studies was to determine whether hepatic ACAT2 is rate-limiting in all three of these important routes of cholesterol homeostasis. Liver-specific depletion of ACAT2 resulted in reduced packaging of cholesterol into apoB-containing lipoproteins (very low density lipoprotein, intermediate density lipoprotein, and low density lipoprotein), whereas high density lipoprotein cholesterol levels remained unchanged. In the liver of ACAT2 ASO-treated mice, cholesterol ester accumulation was dramatically reduced, yet there was no reciprocal accumulation of unesterified cholesterol. Paradoxically, ASO-mediated depletion of hepatic ACAT2 promoted fecal neutral sterol excretion without altering biliary sterol secretion. Interestingly, during isolated liver perfusion, ACAT2 ASO-treated livers had augmented secretion rates of unesterified cholesterol and phospholipid. Furthermore, we demonstrate that liver-derived cholesterol from ACAT2 ASOtreated mice is preferentially delivered to the proximal small intestine as a precursor to fecal excretion. Collectively, these studies provide the first insight into the hepatic itinerary of cholesterol when cholesterol esterification is inhibited only in the liver, and provide evidence for a novel non-biliary route of fecal sterol loss.

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“…Parsippany, N.J., USA) after a right-kidney nephrec tomy. Thereafter the animals in all experimental groups were maintained in individual metabolic cages and fed a cholesterol-free pellet diet of known compo sition (% of weight): casein (35), cotton-seed oil (3), starch (50), and methylcellulose, mineral salts, and vitamins (12). Bile fistula rats were randomly divided into two groups: (1) bile fistula controls (BF: n = 7) and (2) rats fed sodium taurocholatc inherent to the diet providing 50 mg/100 g of diet (BF,C : n = 6).…”

Section: Methodsmentioning

confidence: 99%

“…In addition, mucosal cholesterol can be carried to the lymph system or diverted into the lumen inherent to the sloughing off of mucosal cells [5][6][7], It has been a controversial matter which is the major sterol controlling the intestinal mucosal cholesterol synthesis: cholesterol from diet and bile [8][9][10] or from bile acids [11], Dogs submitted to bile duct-ureter fistula, in the absence of dietary cholesterol, mark edly increased their whole-body cholesterol production, as expected, but surprisingly the fecal excretion of cholesterol also rose [12]. Since luminal cholesterol might also origi nate from filtration of plasma lipoprotein through the mucosal wall, in addition to the local mucosal synthesis, we have submitted rats to bile diversion aiming at measuring (l)th e mucosal synthesis free from inhibi tion either by exogenous cholesterol or by bile acids and (2) the role of bile acids in the control of the mucosal cholesterol syn thesis.…”

mentioning

confidence: 97%

Bile Acids Do Not Regulate the Intestinal Mucosal Cholesterol Synthesis: Studies in the Chronic Bile Duct-Ureter Fistula Rat Model

et al. 1990

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Control male Wistar rats with intact bile circulation, animals with a bile duct-right ureter fistula, and bile duct-right ureter fistula rats fed taurocholic acid (5.5 mg/day) were maintained on a cholesterol-free pellet diet and pulse labeled subcutaneously with radioactive cholesterol. Bile acid feeding did not interfere with the synthesis of cholesterol by the intestinal mucosa or by the whole body in spite of markedly lowering the production of bile acids. Of the total fecal cholesterol mass in bile fistula animals roughly 25% originated from plasma filtration and 75% was ascribed to local mucosal cholesterol synthesis.

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Regulation of Cholesterol Metabolism in the Dog

Cited by 62 publications

References 13 publications

Two independent lipoprotein receptors on hepatic membranes of dog, swine, and man. Apo-B,E and apo-E receptors.

Two independent lipoprotein receptors on hepatic membranes of dog, swine, and man. Apo-B,E and apo-E receptors.

Targeted Depletion of Hepatic ACAT2-driven Cholesterol Esterification Reveals a Non-biliary Route for Fecal Neutral Sterol Loss

Bile Acids Do Not Regulate the Intestinal Mucosal Cholesterol Synthesis: Studies in the Chronic Bile Duct-Ureter Fistula Rat Model

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