Atherosclerosis in genetically obese mice: The mutants obese, diabetes, fat, tubby, and lethal yellow

Nishina, Patsy M.; Naggert, Jiirgen K.; Verstuyft, Judy G.; Paigen, Beverly

doi:10.1016/0026-0495(94)90195-3

Cited by 106 publications

(97 citation statements)

References 20 publications

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“…The low incidence of gallstone formation in WT mice observed in our study is mainly attributed to the feeding of a semisynthetic and refined PLD as compared with lithogenic diets used in other studies (35,36). Because the fat content is derived primarily from cocoa butter, this purified diet has been shown to consistently reduce liver damage and gallstone formation in this strain (37,38). There was a 28% increase in plasma cholesterol concentrations and a 39% decrease in plasma TG concentrations in PKC␤ Ϫ/Ϫ mice as compared with WT mice fed PLD ( Fig.…”

Section: Genotypementioning

confidence: 59%

Disruption of the Murine Protein Kinase Cβ Gene Promotes Gallstone Formation and Alters Biliary Lipid and Hepatic Cholesterol Metabolism

Huang¹,

Bansode

Rowland

et al. 2011

Journal of Biological Chemistry

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The protein kinase C (PKC) family of Ca 2؉ and/or lipid-activated serine-threonine protein kinases is implicated in the pathogenesis of obesity and insulin resistance. We recently reported that protein kinase C␤ (PKC␤), a calcium-, diacylglycerol-, and phospholipid-dependent kinase, is critical for maintaining whole body triglyceride homeostasis. We now report that PKC␤ deficiency has profound effects on murine hepatic cholesterol metabolism, including hypersensitivity to diet-induced gallstone formation. The incidence of gallstones increased from 9% in control mice to 95% in PKC␤ ؊/؊ mice. Gallstone formation in the mutant mice was accompanied by hyposecretion of bile acids with no alteration in fecal bile acid excretion, increased biliary cholesterol saturation and hydrophobicity indices, as well as hepatic p42/44 MAPK activation, all of which enhance susceptibility to gallstone formation. Lithogenic diet-fed PKC␤ ؊/؊ mice also displayed decreased expression of hepatic cholesterol-7␣-hydroxylase (CYP7A1) and sterol 12␣-hydroxylase (CYP8b1). Finally, feeding a modified lithogenic diet supplemented with milk fat, instead of cocoa butter, both increased the severity of and shortened the interval for gallstone formation in PKC␤ ؊/؊ mice and was associated with dramatic increases in cholesterol saturation and hydrophobicity indices. Taken together, the findings reveal a hitherto unrecognized role of PKC␤ in fine tuning diet-induced cholesterol and bile acid homeostasis, thus identifying PKC␤ as a major physiological regulator of both triglyceride and cholesterol homeostasis.

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Section: Genotypementioning

confidence: 59%

Disruption of the Murine Protein Kinase Cβ Gene Promotes Gallstone Formation and Alters Biliary Lipid and Hepatic Cholesterol Metabolism

Huang¹,

Bansode

Rowland

et al. 2011

Journal of Biological Chemistry

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“…The OB Ϫ/Ϫ mice had increased levels of HDL with a marked decrease in VLDL-TG relative to WT mice, and thus were particularly resistant to the development of atherosclerotic lesions. 46 Higher serum TG is a risk factor for atherosclerosis, which was elevated in OB Ϫ/Ϫ /SHP Ϫ/Ϫ mice as compared with OB Ϫ/Ϫ mice. However, this elevation did not reach higher statistical significance than WT controls.…”

Section: Discussionmentioning

confidence: 94%

Molecular characterization of the role of orphan receptor small heterodimer partner in development of fatty liver

et al. 2007

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The orphan receptor Small Heterodimer Partner (SHP, NROB2) regulates metabolic pathways, including hepatic bile acid, lipid, and glucose homeostasis. We reported that SHP-deletion in leptin-deficient OB ؊/؊ mice increases insulin sensitivity, and prevents the development of fatty liver. The prevention of steatosis in OB ؊/؊ /SHP ؊/؊ double mutants is not due to decreased body weight but is associated with increased hepatic very-low-density lipoprotein (

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“…42 Intriguingly, leptin-deficient ob/ob mice or leptin-receptor deficient db/db mice are relatively resistant to atherosclerosis despite being obese, hyperlipidemic and diabetic. 43 Furthermore, carotid artery injury combined with cholesterol and high-fat diet in ob/ob or db/db mice failed to induce significant neointimal thickening whereas the same treatment was very effective in wild-type mice. 44 To complicate the matter, obese subjects are known to develop leptin resistance; the role of leptin in promoting atherosclerosis in diet-induced obesity is therefore not clear.…”

Section: Ectopic Fat Storage In the Heartmentioning

confidence: 99%

Ectopic fat storage in heart, blood vessels and kidneys in the pathogenesis of cardiovascular diseases

et al. 2004

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In humans and most animal models, the development of obesity leads not only to increased fat depots in classical adipose tissue locations but also to significant lipid deposits within and around other tissues and organs, a phenomenon known as ectopic fat storage. The purpose of this review is to explore the possible locations of ectopic fat in key target-organs of cardiovascular control (heart, blood vessels and kidneys) and to propose how ectopic fat storage can play a role in the pathogenesis of cardiovascular diseases associated with obesity. In animals fed a high-fat diet, cardiac fat depots within and around the heart impair both systolic and diastolic functions, and may in the long-term promote heart failure. Accumulation of fat around blood vessels (perivascular fat) may affect vascular function in a paracrine manner, as perivascular fat cells secrete vascular relaxing factors, proatherogenic cytokines and smooth muscle cell growth factors. Furthermore, high amounts of perivascular fat could mechanically contribute to the increased vascular stiffness seen in obesity. Finally, accumulation of fat in the renal sinus may limit the outflow of blood and lymph from the kidney, which would alter intrarenal physical forces and promote sodium reabsorption and arterial hypertension. Taken together, ectopic fat storage in key target-organs of cardiovascular control may impair their functions, contributing to the increased prevalence of cardiovascular diseases in obese subjects.

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Atherosclerosis in genetically obese mice: The mutants obese, diabetes, fat, tubby, and lethal yellow

Cited by 106 publications

References 20 publications

Disruption of the Murine Protein Kinase Cβ Gene Promotes Gallstone Formation and Alters Biliary Lipid and Hepatic Cholesterol Metabolism

Disruption of the Murine Protein Kinase Cβ Gene Promotes Gallstone Formation and Alters Biliary Lipid and Hepatic Cholesterol Metabolism

Molecular characterization of the role of orphan receptor small heterodimer partner in development of fatty liver

Ectopic fat storage in heart, blood vessels and kidneys in the pathogenesis of cardiovascular diseases

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