Metabolic adaptations to dietary fat malabsorption in chylomicron-deficient mice

Jung, Hye Rim; Turner, Scott; Neese, Richard A.; Young, Steven G.; Hellerstein, Marc K.

doi:10.1042/bj3430473

Cited by 28 publications

(22 citation statements)

References 24 publications

(34 reference statements)

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“…To determine de novo synthesis of cholesterol and bile salts, mice were fed a diet containing [1-13 C]acetate for 10 days (20 mg/g chow ) (33). Animals ate the diet in normal quantities and grew normally.…”

Section: Methodsmentioning

confidence: 99%

Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL

Groen¹,

Bloks²,

Bandsma³

et al. 2001

J. Clin. Invest.

133

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The ABC transporter ABCA1 regulates HDL levels and is considered to control the first step of reverse cholesterol transport from the periphery to the liver. To test this concept, we studied the effect of ABCA1 deficiency on hepatic metabolism and hepatobiliary flux of cholesterol in mice. Hepatic lipid contents and biliary secretion rates were determined in Abca1 -/-, Abca1 +/-, and Abca1 +/+ mice with a DBA background that were fed either standard chow or a high-fat, high-cholesterol diet. Hepatic cholesterol and phospholipid contents in Abca1 -/-mice were indistinguishable from those in Abca1 +/-and Abca1 +/+ mice on both diets. In spite of the absence of HDL, biliary secretion rates of cholesterol, bile salts, and phospholipid were unimpaired in Abca1 -/-mice. Neither the hepatic expression levels of genes controlling key steps in cholesterol metabolism nor the contribution of de novo synthesis to biliary cholesterol and bile salts were affected by Abca genotype. Finally, fecal excretion of neutral and acidic sterols was similar in all groups. We conclude that plasma HDL levels and ABCA1 activity do not control net cholesterol transport from the periphery via the liver into the bile, indicating that the importance of HDL in reverse cholesterol transport requires re-evaluation.

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Section: Methodsmentioning

confidence: 99%

Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL

Groen¹,

Bloks²,

Bandsma³

et al. 2001

J. Clin. Invest.

133

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“…The samples were vortexed, incubated at room temperature overnight, and centrifuged for 3 min at 900 ϫ g. The liquid portion was transferred to a glass tube and dried under nitrogen. The samples were then resuspended in 1.0 ml of heptane, and the fatty acid methyl esters were quantified by gas chromatography (23). After normalization of the data to the C-15 internal standard, triglyceride measurements were calculated as M of triglyceride/g of liver tissue.…”

Section: Methodsmentioning

confidence: 99%

A Deficiency of Microsomal Triglyceride Transfer Protein Reduces Apolipoprotein B Secretion

Leung¹,

Véniant²,

Kim³

et al. 2000

Journal of Biological Chemistry

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Microsomal triglyceride transfer protein (MTP) transfers lipids to apolipoprotein B (apoB) within the endoplasmic reticulum, a process that involves direct interactions between apoB and the large subunit of MTP. Recent studies with heterozygous MTP knockout mice have suggested that half-normal levels of MTP in the liver reduce apoB secretion. We hypothesized that reduced apoB secretion in the setting of half-normal MTP levels might be caused by a reduced MTP:apoB ratio in the endoplasmic reticulum, which would reduce the number of apoB-MTP interactions. If this hypothesis were true, half-normal levels of MTP might have little impact on lipoprotein secretion in the setting of halfnormal levels of apoB synthesis (since the ratio of MTP to apoB would not be abnormally low) and might cause an exaggerated reduction in lipoprotein secretion in the setting of apoB overexpression (since the MTP:apoB ratio would be even lower). To test this hypothesis, we examined the effects of heterozygous MTP deficiency on apoB metabolism in the setting of normal levels of apoB synthesis, half-normal levels of apoB synthesis (heterozygous Apob deficiency), and increased levels of apoB synthesis (transgenic overexpression of human apoB). Contrary to our expectations, half-normal levels of MTP reduced the plasma apoB100 levels to the same extent (ϳ25-35%) at each level of apoB synthesis. In addition, apoB secretion from primary hepatocytes was reduced to a comparable extent at each level of apoB synthesis. Thus, these results indicate that the concentration of MTP within the endoplasmic reticulum rather than the MTP:apoB ratio is the critical determinant of lipoprotein secretion. Finally, we found that heterozygosity for an apoB knockout mutation lowered plasma apoB100 levels more than heterozygosity for an MTP knockout allele. Consistent with that result, hepatic triglyceride accumulation was greater in heterozygous apoB knockout mice than in heterozygous MTP knockout mice. Microsomal triglyceride transfer protein (MTP)1 is expressed at high levels in the absorptive enterocytes of the intestine and hepatocytes, at moderate levels in the visceral endoderm of the yolk sac during embryonic development, and at relatively low levels in kidney and cardiac muscle (1-4). In each of these tissues, MTP plays a key role in the assembly and secretion of apoB-containing lipoproteins (1, 3, 5). MTP is located within the lumen of the endoplasmic reticulum (ER) and is thought to transfer lipids to apoB as that molecule is translated, allowing apoB to assume a proper conformation for forming a spherical lipoprotein with a neutral lipid core (6). In the absence of MTP, triglyceride-rich, apoB-containing lipoproteins cannot be assembled or secreted (3, 6, 7). The mechanism of MTP action has attracted considerable scrutiny. Of note, several lines of evidence have suggested that the assembly of lipoproteins involves a direct interaction between MTP and apoB. First, Wu et al. (8) demonstrated that apoB can be immunoprecipitated from the microsomes of cult...

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“…Fatty acids attached to the sn-2 position may be preferentially transported to the liver instead of extrahepatic organs because of the positional specificity of lipoprotein lipase for the sn-1 and sn-3 positions of TAG. The residual TAG remaining in the chylomicron remnant after lipoprotein lipase action are an important source of hepatic fatty acids and are estimated to account for 73% of the newly-synthesised VLDL-TAG in mice (Jung et al 1999). Mortimer et al (1994) have reported that the plasma clearance of TAG-rich lipoproteins depends on the positional composition of the TAG rather than the overall saturation of the TAG.…”

Section: Triacylglycerol Structurementioning

confidence: 99%

Influence of triacylglycerol structure of stearic acid-rich fats on postprandial lipaemia

Berry

Sanders

2005

Proc. Nutr. Soc.

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Exaggerated postprandial lipaemia may increase the risk of CHD by contributing to both thrombotic and atherogenic processes. Previous research has focused on the quantity and composition of dietary fat, whereas the effect of triacylglycerol (TAG) structure on postprandial lipaemia and clotting factor VII activity has received little attention. TAG with similar fatty acid composition may have different biochemical and physical properties that are dependent on their TAG structure, and these differences may affect lipid metabolism. Recent findings suggest that differences in the physical properties of stearic acid-rich fats are associated with differences in postprandial lipaemia, and may play an important role in determining their rates of digestion and absorption.

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Metabolic adaptations to dietary fat malabsorption in chylomicron-deficient mice

Cited by 28 publications

References 24 publications

Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL

Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL

A Deficiency of Microsomal Triglyceride Transfer Protein Reduces Apolipoprotein B Secretion

Influence of triacylglycerol structure of stearic acid-rich fats on postprandial lipaemia

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