A genetic model for absent chylomicron formation: mice producing apolipoprotein B in the liver, but not in the intestine.

Young, Stephen G.; Cham, Candace M.; Pitas, Robert E.; Burri, Betty J.; Connolly, Andrew J.; Flynn, Laura M.; Pappu, Anuradha S.; Wong, Jinny S.; Hamilton, Robert L.; Farese, Robert V.

doi:10.1172/jci118365

Cited by 118 publications

(122 citation statements)

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“…Consequently, Apob 100/100 mice excrete a significantly greater amount of fecal neutral steroids than wild-type and Apob 48/48 mice, and increased excretion of these steroids may reduce cholesterol accumulation in the body. 31 Moreover, in an experiment with a small number of mice, Young et al 14 found that disruption of the APO-B gene significantly inhibits cholesterol absorption in mice that express a human APO-B transgene in the liver but do not synthesize any APO-B in the intestine. Therefore, our findings support the concept that APO-B48 is essential for the pack- Fig.…”

Section: Discussionmentioning

confidence: 99%

“…13 APO-B48 is principally produced by the intestine and is essential for the packaging of alimentary lipids into chylomicrons. 14,15 After intestinal chylomicrons enter the circulation via the thoracic duct, their triglyceride cores are hydrolyzed by lipoprotein lipase and hepatic lipase. The resulting chylomicron remnants, which are enriched with dietary cholesterol, are efficiently and rapidly cleared from plasma by hepatocytes with a half-life of less than 10 minutes.…”

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confidence: 99%

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Reduced susceptibility to cholesterol gallstone formation in mice that do not produce apolipoprotein B48 in the intestine

Wang

2005

Hepatology

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It has been found that polymorphisms in the apolipoprotein (APO)-B gene are associated with cholesterol gallstones in humans. We hypothesized that APO-B plays a major regulatory role in the response of biliary cholesterol secretion to high dietary cholesterol and contributes to cholesterol gallstone formation. In the present study, we investigated whether lack of expression of intestinal Apob48 or Apob100 reduces susceptibility to cholesterol gallstones by decreasing intestinal absorption and biliary secretion of cholesterol in male mice homozygous for an "APO-B48 only" allele (Apob 48/48 ), an "APO-B100 only" allele (Apob 100/100 ), or a wild-type APO-B allele (Apob ؉/؉ ) before and during an 8-week lithogenic diet. We found that cholesterol absorption was significantly decreased as a result of the APO-B48 deficiency in Apob 100/100 mice compared with wild-type and Apob 48/48 mice, regardless of whether chow or the lithogenic diet was administered. Consequently, hepatic cholesterol synthesis was significantly increased in Apob 100/ 100 mice compared with wild-type and Apob 48/48 mice. On chow, the APO-B100 deficiency in S tudies in humans and inbred mice have demonstrated that a complex genetic basis determines the individual and strain predisposition to develop cholesterol gallstones in response to environmental factors. 1 The primary pathophysiological defect involved in cholesterol gallstone formation is increased biliary secretion of cholesterol from the liver, which produces bile supersaturated with cholesterol. 2 Subsequently, biliary cholesterol precipitates as "anhydrous" and monohydrate crystals, which grow and agglomerate toward the formation of macroscopic stones in the gallbladder. Biliary cholesterol is mostly derived from circulating lipoproteins, which originate from the hepatic uptake of plasma high-density lipoprotein (HDL) and chylomicron remnants. [3][4][5][6][7][8] Thus, the potential interrelationship between lipoprotein metabolism-related genes and cholesterol gallstones requires further investigation. In particular, it has been found that polymorphisms in the apolipoprotein (APO)-B gene are associated with cholesterol gallstones in humans. 9-12 Therefore, we hypothesized that APO-B plays a major regulatory role in the response of biliary cholesterol secretion to high dietary cholesterol and contributes to the formation of cholesterol gallstones. APO-B has two different isoforms, APO-B48 and APO-B100, and plays a particularly critical role in the Abbreviations: APO, apolipoprotein; HDL, VLDL, LDL, mRNA, messenger RNA.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Reduced susceptibility to cholesterol gallstone formation in mice that do not produce apolipoprotein B48 in the intestine

Wang

2005

Hepatology

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“…Accordingly, these mice are unable to form chylomicrons or ef®ciently absorb dietary fat; the result is that CHO represents a high percent of absorbed nutrients. Despite the marked reduction of dietary fat absorption (estimated to be 10 ± 20% of normal, based on serum concentrations of lipid-soluble vitamins), these animals maintain normal plasma concentration of triglycerides and cholesterol and are able to accumulate body fat, though at a much lower rate than in normal mice (Young et al, 1995). These observations suggested that DNL might occur at a very high rate, to maintain hepatic lipoprotein secretion and adipose fat deposition.…”

Section: Unanswered Questions Concerning the Regulation And Functionsmentioning

confidence: 98%

“…Young et al have developed a mouse with the endogenous apoB gene knocked out and a human apoB transgene expressed in liver only (Young et al, 1995). Accordingly, these mice are unable to form chylomicrons or ef®ciently absorb dietary fat; the result is that CHO represents a high percent of absorbed nutrients.…”

Section: Unanswered Questions Concerning the Regulation And Functionsmentioning

confidence: 99%

De novo lipogenesis in humans: metabolic and regulatory aspects

1999

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The enzymatic pathway for converting dietary carbohydrate (CHO) into fat, or de novo lipogenesis (DNL), is present in humans, whereas the capacity to convert fats into CHO does not exist. Here, the quantitative importance of DNL in humans is reviewed, focusing on the response to increased intake of dietary CHO. Eucaloric replacement of dietary fat by CHO does not induce hepatic DNL to any substantial degree. Similarly, addition of CHO to a mixed diet does not increase hepatic DNL to quantitatively important levels, as long as CHO energy intake remains less than total energy expenditure (TEE). Instead, dietary CHO replaces fat in the whole-body fuel mixture, even in the post-absorptive state. Body fat is thereby accrued, but the pathway of DNL is not traversed; instead, a coordinated set of metabolic adaptations, including resistance of hepatic glucose production to suppression by insulin, occurs that allows CHO oxidation to increase and match CHO intake. Only when CHO energy intake exceeds TEE does DNL in liver or adipose tissue contribute signi®cantly to the wholebody energy economy. It is concluded that DNL is not the pathway of ®rst resort for added dietary CHO, in humans. Under most dietary conditions, the two major macronutrient energy sources (CHO and fat) are therefore not interconvertible currencies; CHO and fat have independent, though interacting, economies and independent regulation. The metabolic mechanisms and physiologic implications of the functional block between CHO and fat in humans are discussed, but require further investigation. IntroductionIn this review, I will address the fate of surplus dietary carbohydrate (CHO) in humans. More speci®cally, the focus will be on conversion of CHO to fat, or de novo lipogenesis (DNL), with the question framed in quantitative terms: to what extent is surplus dietary CHO energy converted to fat? The various ways in which CHO content of the diet can be increased will be considered: increased CHO that replaces dietary fat (high-CHO low-fat, eucaloric diets); CHO added to a mixed diet, where CHO energy is less than total energy expenditure (TEE) but total energy intake exceeds TEE; and CHO consumption in excess of TEE. This review will therefore focus on the upper limits and consequences of increased CHO intake rather than on the lower limits and consequences of insuf®cient fat intake. Background and historical review

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“…Genetically altered mice have been reported that lack various apoproteins or lipoprotein receptors, that are deficient in canalicular lipid transporters, that are defective in the promoters that regulate bile acid synthesis, and that have deletions of one of the major pathways for the formation of acidic sterols. [30][31][32][33][34][35][36] These models offer powerful tools for understanding the molecular mechanisms of cellular sterol balance. Unfortunately, however, there exist very few published data describing the comparative features of bile acid metabolism and its regulation in this species.…”

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confidence: 99%

Gender-related differences in bile acid and sterol metabolism in outbred CD-1 mice fed low- and high-cholesterol diets

Turley¹,

Schwarz

Spady³

et al. 1998

Hepatology

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These studies were undertaken to determine whether in young adult outbred CD-1 mice there were any genderrelated differences in basal bile acid metabolism that might be important in determining how males and females in this species responded to a dietary cholesterol challenge. When fed a plain cereal-based rodent diet without added cholesterol, 3-month-old females, compared with age-matched males, manifested a significantly larger bile acid pool (89.1 vs. 54.1 mol/100 g body weight), a higher rate of fecal bile acid excretion (13.6 vs. 8.5 mol/d/100 g body weight), a more efficient level of intestinal cholesterol absorption (41.1% vs. 25.3%), and a lower rate of hepatic sterol synthesis (338 vs. 847 nmol/h/g). Similar results were found in C57BL/6 and 129Sv inbred mice. In matching groups of CD-1 mice fed a diet containing 1% cholesterol for 21 days, hepatic cholesterol levels increased much more in the females (from 2.4 to 9.1 mg/g) than in the males (from 2.1 to 5.2 mg/g). This occurred even though the level of stimulation of cholesterol 7␣-hydroxylase activity in the females (79%) exceeded that in the males (55%), as did the magnitude of the increase in fecal bile acid excretion (females: 262% vs. males: 218%). However, in both sexes, bile acid pool size expanded only modestly and by a comparable degree (females: 19% vs. males: 26%) so that in the cholesterol-fed groups, the pool remained substantially larger in the females than in the males (102.3 vs. 67.6 mol/100 g body weight). Together, these data demonstrate that while male and female CD-1 mice do not differ qualitatively in the way cholesterol feeding changes their bile acid metabolism, the inherently larger bile acid pool in the female likely facilitates the delivery of significantly more dietary cholesterol to the liver than is the case in males, thereby resulting in higher steady-state hepatic cholesterol levels. (HEPATOLOGY 1998;28:1088-1094.)The central role that the liver plays in the maintenance of whole-body sterol balance and the regulation of plasma low-density lipoprotein (LDL)-cholesterol levels stems partly from its unique ability to convert cholesterol to bile acids, the excretion of which represents a major route for the elimination of cholesterol from the body.

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A genetic model for absent chylomicron formation: mice producing apolipoprotein B in the liver, but not in the intestine.

Cited by 118 publications

References 46 publications

Reduced susceptibility to cholesterol gallstone formation in mice that do not produce apolipoprotein B48 in the intestine

Reduced susceptibility to cholesterol gallstone formation in mice that do not produce apolipoprotein B48 in the intestine

De novo lipogenesis in humans: metabolic and regulatory aspects

Gender-related differences in bile acid and sterol metabolism in outbred CD-1 mice fed low- and high-cholesterol diets

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