Predominantly Increased Triglyceride-rich Lipoproteins Induced by Dietary Cholesterol Promoted Atherosclerosis Formation in LDL Receptor Knockout Golden Hamster

Q: What are the key findings of this study?

Ezetimibe reduced aortic root atherosclerotic lesion area by 75% and full-length aorta lesion area by 50% in high-cholesterol, high-fat diet-fed LDLR knockout golden hamsters.

Q: What is the clinical evidence from this study?

Population: Mixed hyperlipidemia and atherosclerosis (n=50). Intervention: Ezetimibe vs. Saline vehicle control (on high-cholesterol high-fat diet or chow diet). Primary outcome: Atherosclerotic lesion area in the aortic root and full-length aorta (en face) (75% reduction in aortic root lesion area; 50% reduction in full-length aorta lesion area, p=<=0.05).

Q: What does this research mean for the field?

Ezetimibe reduces aortic root atherosclerotic lesion area by 75% and full-length aorta lesion area by 50% by selectively decreasing dietary cholesterol-induced triglyceride-rich lipoproteins in LDLR-knockout golden hamsters. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

Investigate the atherogenic properties of dietary cholesterol-induced triglyceride-rich lipoproteins and their clearance mechanism in LDL receptor-knockout golden hamsters.

Yuhui Wang; Ping Ma; Jinjie Wang; Kunxiang He; Gonglie Chen; Wei Y. Huang; Jianglin Fan; Xunde Xian; Chaojie Liu

doi:10.21203/rs.3.rs-238928/v1

June 25, 2021Open Access

Predominantly Increased Triglyceride-rich Lipoproteins Induced by Dietary Cholesterol Promoted Atherosclerosis Formation in LDL Receptor Knockout Golden Hamster

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Key result

Ezetimibe cuts aortic root atherosclerotic lesion area by ~75% in hyperlipidemic LDLR-knockout hamsters.

75% reduction in aortic root lesion area; 50% reduction in full-length aorta lesion area
P<=0.05
n=50

Why the study?

Although elevated triglyceride is an independent cardiovascular risk factor, distinguishing the in vivo effects of different lipoproteins experimentally is difficult, leaving the role of triglyceride-rich lipoproteins in atherosclerosis incompletely understood.

Key Points

Investigate the atherogenic properties of dietary cholesterol-induced triglyceride-rich lipoproteins and their clearance mechanism in LDL receptor-knockout golden hamsters.
Assessed lipoprotein and apolipoprotein profiles in wild-type and LDLR−/− golden hamsters fed chow or high-cholesterol high-fat (HCHF) diets.
Treated LDLR−/− hamsters on a 40-day HCHF diet with or without ezetimibe to measure aortic plaque development, hepatic steatosis, and endothelial cell activation.
HCHF diet raised total cholesterol and triglycerides above 3000 mg/dL in LDLR−/− hamsters, driven predominantly by increases in ApoB48- and ApoE-rich chylomicrons and VLDL remnants rather than LDL.
Ezetimibe administration significantly decreased aortic atherosclerotic lesion area by 75% in the aortic root and 50% across the full aortic length.
Ezetimibe treatment reduced hepatic triglycerides by about 31% and hepatic cholesterol by 45% in HCHF-fed LDLR−/− hamsters while suppressing endothelial ICAM-1 and VCAM-1 expression.

PICO

P

Population

50 female Syrian golden hamsters (30 LDLR-/- and 20 wild-type) aged 12 months fed a chow or high-cholesterol high-fat diet with or without ezetimibe for 40 days.

I

Intervention / Comparator

Ezetimibe vs Saline vehicle control (on high-cholesterol high-fat diet or chow diet) (2 mg/kg/day (hamsters), 3 mg/kg/day (mice))

O

Primary Outcome

Atherosclerotic lesion area in the aortic root and full-length aorta (en face) — 75% reduction in aortic root lesion area; 50% reduction in full-length aorta lesion area, p=<=0.05

Main Result

Effect estimate: 75% reduction in aortic root lesion area; 50% reduction in full-length aorta lesion area

p-value: p=<=0.05

Limitations

Preclinical animal model study in golden hamsters and mice, limiting direct clinical extrapolation to humans
Plasma lipoproteins in the LDLR-/- high-fat diet group were too large for direct FPLC column loading, requiring pre-centrifugation that removed approximately 50% of estimated lipid concentrations
Evaluation of triglyceride-rich lipoprotein atherogenicity in the LDLR-/- hamster model was conducted on a background of high baseline LDL-C levels
In wild-type hamsters, both VLDL and LDL increased after the high-cholesterol high-fat diet, making their individual atherogenic roles indistinguishable in the wild-type model

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Implication

Ezetimibe may mitigate remnant-driven atherosclerosis in this model; leaves open human translation and clinical testing.

Abstract

Epidemiological investigation showed that triglyceride is an independent risk factor of cardiovascular diseases, but it is difficult to distinguish the effects of different lipoproteins by an experimental system in vivo, the role of triglyceride-rich lipoproteins (TRLs) in atherosclerosis have not been fully understood. Here we found LDL receptor knock-out (LDLR−/−) hamsters have special characteristics of lipid profile for investigating effects of TRLs. Mixed hyperlipidemia in LDLR−/− hamsters after high cholesterol and high fat (HCHF) diet were marked by increasing of chylomicrons, VLDL and their remnants, but not LDL. Ezetimibe treatment significantly decreased these large particles containing ApoB and ApoE without affecting LDL, leading to the dramatic reduction of plasma cholesterol and triglycerides. 40 days of HCHF diet feeding accelerated aortic atherosclerosis accompanied severe fatty liver, and ezetimibe treatment inhibited their development. Also, TRLs lowering inhibited the expression of vascular adhesion factors and lipid uptake of macrophage. Our results suggest that golden hamster is a proper model for studying hypertriglyceridemia related diseases. In LDLR−/− hamster, TRLs showed independent atherogenicity by triggering inflammatory response of endothelial cells and the formation of foam cells from macrophages. And these TRLs clearance is mediated by LDL receptor. TRLs would be an important therapeutic target for atherosclerotic development with postprandial hyperlipidemia.

Discussion

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Cite This Study

Wang et al. (2021) studied Mixed hyperlipidemia and atherosclerosis (n=50). Ezetimibe vs. Saline vehicle control (on high-cholesterol high-fat diet or chow diet) was evaluated on Atherosclerotic lesion area in the aortic root and full-length aorta (en face) (75% reduction in aortic root lesion area; 50% reduction in full-length aorta lesion area, p=<=0.05). Ezetimibe reduced aortic root atherosclerotic lesion area by 75% and full-length aorta lesion area by 50% in high-cholesterol, high-fat diet-fed LDLR knockout golden hamsters.

synapsesocial.com/papers/6ae178e18635ef7c49818947 https://doi.org/10.21203/rs.3.rs-238928/v1

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Predominantly Increased Triglyceride-rich Lipoproteins Induced by Dietary Cholesterol Promoted Atherosclerosis Formation in LDL Receptor Knockout Golden Hamster

Key Points

PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Predominantly Increased Triglyceride-rich Lipoproteins Induced by Dietary Cholesterol Promoted Atherosclerosis Formation in LDL Receptor Knockout Golden Hamster

Key Points

PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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