Differing rates of cholesterol absorption among inbred mouse strains yield differing levels of HDL-cholesterol

Sontag, Timothy J.; Chellan, Bijoy; Getz, Godfrey S.; Reardon, Catherine A.

doi:10.1194/jlr.m040055

Cited by 13 publications

(15 citation statements)

References 38 publications

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“…Unknown is whether cholesterol transport is altered with the addition of dietary TAG in G5/G8 KO animals. The question of whether cholesterol transport can be altered in the presence of TAG was also posed by Sontag et al [41], which they believed cholesterol absorption rates are different in delivery vehicles using medium-chain TAG versus long-chain TAG.…”

Section: Discussionmentioning

confidence: 99%

ABCG5/G8 Deficiency in Mice Reduces Dietary Triacylglycerol and Cholesterol Transport into the Lymph

Zhang

Yang

et al. 2015

Lipids

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The adenosine triphosphate-binding cassette (ABC) transporter G5/G8 is critical in protecting the body from accumulating dietary plant sterols. Expressed in the liver and small intestine, it transports plant sterols into the biliary and intestinal lumens, thus promoting their excretion. The extent to which G5/G8 regulates cholesterol absorption remains unclear. G5/G8 is also implicated in reducing the absorption of dietary triacylglycerols (TAG) by unknown mechanisms. We hypothesized that G5/G8 suppresses the production of chylomicrons, and its deficiency would enhance the absorption of both dietary TAG and cholesterol. The aim of this study was to investigate the effects of G5/G8 deficiency on lipid uptake and secretion into the lymph under steady-state conditions. Surprisingly, compared with wild-type mice (WT) (n = 9), G5/G8 KO (n = 13) lymph fistula mice given a continuous intraduodenal infusion of [3H]-TAG and [14C]-cholesterol showed a significant (P < 0.05) reduction in lymphatic transport of both [3H]-TAG and [14C]-cholesterol, concomitant with a significant (P < 0.05) increase of [3H]-TAG and [14C]-cholesterol accumulated in the intestinal lumen. There was no difference in the total amount of radiolabeled lipids retained in the intestinal mucosa between the two groups. G5/G8 KO mice given a bolus of TAG showed reduced intestinal TAG secretion compared with WT, suggesting an independent role for G5/G8 in facilitating intestinal TAG transport. Our data demonstrate that G5/G8 deficiency reduces the uptake and secretion of both dietary TAG and cholesterol by the intestine, suggesting a novel role for the sterol transporter in the formation and secretion of chylomicrons.

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Section: Discussionmentioning

confidence: 99%

ABCG5/G8 Deficiency in Mice Reduces Dietary Triacylglycerol and Cholesterol Transport into the Lymph

Zhang

Yang

et al. 2015

Lipids

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“…For the atherosclerosis experiments, all animals were fed the Western-type diet (WTD) because apoA-I-deficient mice have low plasma cholesterol levels, perhaps attributable to reduced cholesterol absorption. 17 In Tables 1 and 2, we report body weight, plasma cholesterol, and triglyceride in each of the 4 genotypes at baseline or 6 and 10 weeks after the initiation of the WTD. The mice in the FVB background weighed more than the mice in the C57 background on chow, but this difference was attenuated by WTD administration.…”

Section: Resultsmentioning

confidence: 99%

“…Also, FVB intestine expresses higher levels of apoA-IV, apoC-II, and apoC-III. 17 There may be other putative acceptors. Further explorations are required to elucidate the detailed cholesterol homeostatic mechanisms in these mice.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein A-I Protection Against Atherosclerosis Is Dependent on Genetic Background

Sontag

Krishack

Lukens

et al. 2014

ATVB

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Objective— Inbred mouse strains have different susceptibilities to experimental atherosclerosis. The C57BL/6 strain is among the most sensitive and has, therefore, been the most widely used in atherosclerosis studies, whereas many strains are resistant. The FVB/N strain is highly resistant to atherosclerosis on the apolipoprotein E (apoE)– and low-density lipoprotein (LDL) receptor–deficient backgrounds. High-density lipoprotein and its major apoprotein, apoA-I, have been shown to be protective against atherogenesis on the C57BL/6 background. We here examine the influence of genetic background on the atheroprotective nature of apoA-I. Approach and Results— ApoE-deficient/apoA-I-deficient mice were generated in the C57BL/6 and FVB/N strains from apoE-deficient mice. After 6 to 10 weeks on a Western-type diet, plasma lipids and atherosclerotic lesion size were assessed. Macrophage recruitment, cholesterol regulation, and blood monocyte levels were examined as potential mechanisms driving lesion size differences. FVB/N knockout mice had higher plasma very-LDL/LDL cholesterol than their C57BL/6 counterparts. ApoA-I deficiency decreased very-LDL/LDL cholesterol in C57BL/6 mice but not in FVB/N mice. FVB/N single and double knockout mice had less lesion than C57BL/6 6 to 10 weeks on diet. ApoA-I deficiency augmented lesion development only in C57BL/6 mice. Macrophage recruitment to thioglycollate-treated peritoneum and diet-induced blood monocyte levels reflected the pattern of lesion development among the 4 genotypes. ApoA-I deficiency increased macrophage cholesterol content only in C57BL/6. FVB/N plasma was a better acceptor for macrophage cholesterol efflux than C57BL/6. Conclusions— ApoA-I is atheroprotective only in certain genetic contexts. In the C57BL/6 context, but not FVB/N, apoA-I decreases inflammatory macrophage recruitment and monocytosis, contributors to lesion formation.

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“…The cholesterol efflux capacity of the two apoA-I proteins did not differ significantly. On the other hand, the absorption of lipids and cholesterol from the intestinal lumen appears to contribute to the larger, cholesteryl ester rich HDL [39], with more cholesterol being absorbed by the small intestine of FVB/N mice. Finally, the enhancement of atherosclerosis due to the absence of apoA-I in Apoe −/− mice fed the western type diet in the two genetic backgrounds was investigated [40].…”

Section: Apoa-i In the Functions Of Hdl Relevant To Atherogenesismentioning

confidence: 99%

Genetic control of apoprotein A-I and atheroprotection: some insights from inbred strains of mice

Getz¹,

Reardon

2017

Current Opinion in Lipidology

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Purpose of review Previous epidemiological studies and studies in experimental animals have provided strong evidence for the atheroprotective effect of HDL and its major apoprotein, apoA-I. Identification of genetic loci associating apoA-I/HDL with cardiovascular disease is needed to establish a causal relationship. Recent findings Pharmacological interventions to increase apoA-I or HDL cholesterol levels in humans are not associated with reduction in atherosclerosis. GWAS studies in humans and hybrid mouse diversity panel (HMDP) studies looking for genetic variants associated with apoA-I or HDL-cholesterol levels with cardiovascular disease and atherosclerosis have not provided strong evidence for their atheroprotective function. Summary These findings indicate that GWAS and HMDP studies identifying possible genetic determinants of HDL and apoA-I function are needed.

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Differing rates of cholesterol absorption among inbred mouse strains yield differing levels of HDL-cholesterol

Cited by 13 publications

References 38 publications

ABCG5/G8 Deficiency in Mice Reduces Dietary Triacylglycerol and Cholesterol Transport into the Lymph

ABCG5/G8 Deficiency in Mice Reduces Dietary Triacylglycerol and Cholesterol Transport into the Lymph

Apolipoprotein A-I Protection Against Atherosclerosis Is Dependent on Genetic Background

Genetic control of apoprotein A-I and atheroprotection: some insights from inbred strains of mice

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