Myocardial Infarction-Prone Watanabe Heritable Hyperlipidemic Rabbits with Mesenteric Fat Accumulation Are a Novel Animal Model for Metabolic Syndrome

Shiomi, Masashi; Kobayashi, Tsutomu; Kuniyoshi, Nobue; Yamada, Satoshi; Ito, Takashi

doi:10.1159/000338767

Cited by 10 publications

(10 citation statements)

References 74 publications

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“…study shows, independent of diet feeding, considerably elevated plasma LDL concentrations in both rabbit groups. WHHLMI rabbits show clinical features of the metabolic syndrome with age: middle-aged rabbits showed more visceral fat accumulation and a higher accumulation of RAM-11 positive macrophages in the MES AT depot and lower plasma insulin levels as compared to adult WHHLMI rabbits [4] . Obesity and insulin resistance can be induced in experimental animals by exposing them to particular high-fat diets.…”

Section: Cardiac Function and Myocardial Fibrosismentioning

confidence: 97%

“…Myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits were reported to spontaneously develop severe coronary atherosclerosis and MI due to selective breeding from the WHHL rabbits, a strain that shows hypercholesterolemia, resulting in coronary atherosclerosis due to a deficiency in the low-density lipoprotein (LDL) receptors [3] . Shiomi et al [4] also reported that these WHHL-MI rabbits are a good model for the metabolic syndrome. 17-to 21-months old rabbits showed higher accumulation of RAM-11 (macrophages/monocytes)-positive mesenteric (MES) AT and lower plasma insulin levels as compared to adult WHHLMI rabbits [4] .…”

Section: Introductionmentioning

confidence: 95%

“…Shiomi et al [4] also reported that these WHHL-MI rabbits are a good model for the metabolic syndrome. 17-to 21-months old rabbits showed higher accumulation of RAM-11 (macrophages/monocytes)-positive mesenteric (MES) AT and lower plasma insulin levels as compared to adult WHHLMI rabbits [4] . 16 weeks exposure of WHHL rabbits to a high-fat and high-fructose diet (HFFD) induced an elevation of plasma lipid levels, impaired glucose tolerance, accumulation of AT and accelerated coronary atherosclerosis in these animals [5] .…”

Section: Introductionmentioning

confidence: 95%

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Prolonged High-Fat Diet Feeding of WHHLMI Rabbits does Not Aggravate Metabolic or Cardiac Dysfunction

Hemmeryckx¹,

Feng²,

Frederix³

et al. 2018

JDO

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Myocardial infarction (MI)-prone Watanabe hereditary hyperlipidemic (WHHLMI) rabbits were reported to spontaneously but slowly develop MI, associated with enhanced coronary atherosclerosis and metabolic syndrome features. Our aim was to accelerate these processes by exposing the rabbits to a high-fat diet (HFD) that was previously shown to induce insulin resistance and cardiac injury in rabbits. HFD feeding for one year was indeed associated with development of obesity (37% increases in body weight, as compared to 3.7% for control standard-fat diet, SFD). On HFD, liver weight and hepatic triglyceride content were significantly higher as compared to SFD, with mild steatosis. Glucose and insulin levels were not markedly different on SFD or HFD, however after 1 year of diet treatment, HFD-fed animals were more glucose intolerant as compared to SFD-fed rabbits. On SFD, the rabbits developed marked thoracic aorta stenosis and calcification of atherosclerotic lesions, which were not aggravated by HFD feeding. Cardiac function analysis by MRI and transthoracic echocardiography did not reveal significant differences between SFD-and HFD-fed rabbits. Thus, the metabolic and cardiac phenotype of WHHLMI rabbits was not aggravated by HFD feeding for one year, and the rabbits did not spontaneously develop diabetes or myocardial infarction.

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Section: Cardiac Function and Myocardial Fibrosismentioning

confidence: 97%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 95%

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Prolonged High-Fat Diet Feeding of WHHLMI Rabbits does Not Aggravate Metabolic or Cardiac Dysfunction

Hemmeryckx¹,

Feng²,

Frederix³

et al. 2018

JDO

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“…The original WHHL rabbit showed the following features: hypercholesterolemia due to LDL receptor deficiency 11,12) , low high-density lipoprotein cholesterol, atherosclerotic lesions on the aorta (Fig. 2) and various arteries except coronary lesions [13][14][15] , and other related diseases, such as xanthoma on tendons of the limb 1,16) osteonecrosis due to the abnormal accumulation of fat in osteocytes and marrow cells 17) , corneal opacities due to the infiltration of macrophages and epithelial cells 18) , sensorineural hearing loss due to inner ear cell damage 19) , and metabolic syndrome-like findings 20,21) . In addition to the characteristics of WHHL rabbits, coronary atherosclerosis occurred in WHHL-CA rabbits 2,3) , and in WHHLMI rabbits, unstable coronary lesions ( Fig.…”

Section: Introductionmentioning

confidence: 99%

The History of the WHHL Rabbit, an Animal Model of Familial Hypercholesterolemia (I) - Contribution to the Elucidation of the Pathophysiology of Human Hypercholesterolemia and Coronary Heart Disease -

Shiomi

2020

JAT

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ReviewAnimal models that closely resemble both human disease findings and their onset mechanism have contributed to the advancement of biomedical science. The Watanabe heritable hyperlipidemic (WHHL) rabbit and its advanced strains (the coronary atherosclerosis-prone and the myocardial infarction-prone WHHL rabbits) developed at Kobe University (Kobe, Japan), an animal model of human familial hypercholesterolemia, have greatly contributed to the elucidation of the pathophysiology of human lipoprotein metabolism, hypercholesterolemia, atherosclerosis, and coronary heart disease, as described below. 1) The main part of human lipoprotein metabolism has been elucidated, and the low-density lipoprotein (LDL) receptor pathway hypothesis derived from studies using fibroblasts was proven in vivo. 2) Oxidized LDL accumulates in the arterial wall, monocyte adhesion molecules are expressed on arterial endothelial cells, and monocyte-derived macrophages infiltrate the arterial intima, resulting in the formation and progression of atherosclerosis. 3) Coronary lesions differ from aortic lesions in lesion composition. 4) Factors involved in the development of atherosclerosis differ between the coronary arteries and aorta. 5)The rupture of coronary lesions requires secondary mechanical forces, such as spasm, in addition to vulnerable plaques. 6) Specific lipid molecules in the blood have been identified as markers of the progression of coronary lesions. At the end of the breeding of the WHHL rabbit family at Kobe University, this review summarizes the history of the development of the WHHL rabbit family and their contribution to biomedical science.

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“…Myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits, which are developed by selective breeding of Watanabe heritable hyperlipidemic (WHHL) rabbits, are an animal model of familial hypercholesterolemia in humans (10). In previous studies, WHHLMI rabbits were used to investigate the progression of coronary atherosclerotic lesions (11) to observe the process of LDL oxidation with a radioiodinated short peptide probe developed (12), and to investigate the relationship between mesenteric fat accumulation and insulin resistance, hyperlipidemia and atherosclerosis (13). These studies revealed that WHHLMI rabbits are potentially useful for the study of myocardial infarction.…”

mentioning

confidence: 99%

Lipidomic analysis of plasma lipoprotein fractions in myocardial infarction-prone rabbits

Takeda

Koike

Izumi

et al. 2015

Journal of Bioscience and Bioengineering

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Lipids play important roles in the body and are transported to various tissues via lipoproteins. It is commonly assumed that alteration of lipid levels in lipoproteins leads to dyslipidemia and serious diseases such as coronary artery disease (CAD). However, lipid compositions in each lipoprotein fraction induced by lipoprotein metabolism are poorly understood. Lipidomics, which involves the comprehensive and quantitative analysis of lipids, is expected to provide valuable information regarding the pathogenic mechanism of CAD. Here, we performed a lipidomic analysis of plasma and its lipoprotein fractions in myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits. In total, 172 lipids in plasma obtained from normal and WHHLMI rabbits were quantified with high throughput and accuracy using supercritical fluid chromatography hybrid quadrupole-Orbitrap mass spectrometry (SFC/Q-Orbitrap-MS). Plasma levels of each lipid class (i.e., phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, lysophosphatidylcholine, lysophosphatidylethanolamine, sphingomyelin, ceramide, triacylglycerol, diacylglycerol, and cholesterol ester, except for free fatty acids) in 21-month-old WHHLMI rabbits were significantly higher than those in normal rabbits. High levels of functional lipids, such as alkyl-phosphatidylcholines, phospholipids including ω-6 fatty acids, and plasmalogens, were also observed in WHHLMI rabbit plasma. In addition, high-resolution lipidomic analysis using very low density lipoprotein (VLDL) and low density lipoprotein (LDL) provided information on the specific molecular species of lipids in each lipoprotein fraction. In particular, higher levels of phosphatidylethanolamine plasmalogens were detected in LDL than in VLDL. Our lipidomics approach for plasma lipoprotein fractions will be useful for in-depth studies on the pathogenesis of CAD.

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Myocardial Infarction-Prone Watanabe Heritable Hyperlipidemic Rabbits with Mesenteric Fat Accumulation Are a Novel Animal Model for Metabolic Syndrome

Cited by 10 publications

References 74 publications

Prolonged High-Fat Diet Feeding of WHHLMI Rabbits does Not Aggravate Metabolic or Cardiac Dysfunction

Prolonged High-Fat Diet Feeding of WHHLMI Rabbits does Not Aggravate Metabolic or Cardiac Dysfunction

The History of the WHHL Rabbit, an Animal Model of Familial Hypercholesterolemia (I) - Contribution to the Elucidation of the Pathophysiology of Human Hypercholesterolemia and Coronary Heart Disease -

Lipidomic analysis of plasma lipoprotein fractions in myocardial infarction-prone rabbits

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