Differential response of two models of genetically modified mice fed with high fat and cholesterol diets: relationship to the study of non-alcoholic steatohepatitis

Rodríguez-Sanabria, Fernando; Rull, Anna; Aragonès, Gerard; Beltrán‐Debón, Raúl; Alonso-Villaverde, Carlos; Camps, Jordi; Joven, Jorge

doi:10.1007/s11010-010-0498-2

Cited by 13 publications

(9 citation statements)

References 25 publications

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“…Fatty infiltration of the liver or steatosis is known to be an independent risk factor for coronary heart disease and atherosclerosis 32, 33 and is a prominent feature in LDLR −/− mice receiving a HFD 34, 35 . Recent reports have shown that reduction of serum lipoprotein levels can prevent steatosis in LDLR −/− mice 36 and may help to prevent the development of hepatic dysfunction in humans with non-alcoholic steatohepatitis 37, 38 .…”

Section: Resultsmentioning

confidence: 99%

“…The striking impact of LDN-193189 upon hepatic steatosis was likely due to its ability to lower serum cholesterol levels, given the established link between serum cholesterol levels and steatosis 34 . With a prevalence of 20-30% in Western adults and 70-90% among obese or diabetic patients, non-alcoholic fatty liver disease (NAFLD) constitutes a novel landmark feature of the metabolic syndrome 51 .…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of Bone Morphogenetic Protein Signaling Reduces Vascular Calcification and Atherosclerosis

Derwall

Malhotra

Lai

et al. 2012

ATVB

192

168

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Objective The expression of bone morphogenetic proteins (BMPs) is enhanced in human atherosclerotic and calcific vascular lesions. While genetic gain- and loss-of-function experiments in mice have supported a causal role of BMP signaling in atherosclerosis and vascular calcification, it remains uncertain whether BMP signaling might be targeted pharmacologically to ameliorate both of these processes. Methods and Results We tested the impact of pharmacologic BMP inhibition upon atherosclerosis and calcification in low density lipoprotein receptor-deficient (LDLR−/−) mice. LDLR−/− mice fed a high-fat diet developed abundant vascular calcification within twenty weeks. Prolonged treatment of LDLR−/− mice with the small molecule BMP inhibitor LDN-193189 was well-tolerated and potently inhibited development of atheroma, as well as associated vascular inflammation, osteogenic activity, and calcification. Administration of recombinant BMP antagonist ALK3-Fc replicated the anti-atherosclerotic and anti-inflammatory effects of LDN-193189. Treatment of human aortic endothelial cells with LDN-193189 or ALK3-Fc abrogated the production of reactive oxygen species (ROS) induced by oxidized LDL, a known early event in atherogenesis. Unexpectedly, treatment of mice with LDN-193189 lowered LDL serum cholesterol by 35% and markedly decreased hepatosteatosis without inhibiting HMG-CoA reductase activity. Treatment with BMP2 increased, whereas LDN-193189 or ALK3-Fc inhibited apolipoprotein B100 secretion in HepG2 cells, suggesting that BMP signaling contributes to the regulation of cholesterol biosynthesis. Conclusions These results definitively implicate BMP signaling in atherosclerosis and calcification, while uncovering a previously unidentified role for BMP signaling in LDL cholesterol metabolism. BMP inhibition may be helpful in the treatment of atherosclerosis and associated vascular calcification.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of Bone Morphogenetic Protein Signaling Reduces Vascular Calcification and Atherosclerosis

Derwall

Malhotra

Lai

et al. 2012

ATVB

192

168

View full text Add to dashboard Cite

show abstract

“…Previous studies indicate that compared with wildtype mice, LDLR Ϫ/Ϫ mice are more susceptible to obesity with moderate insulin resistance and severe hepatic steatosis due to hyperlipidemia after feeding a type 2 diabetogenic diet, such as a high-fat/highsucrose (HFHS) diet (25)(26)(27). This animal model has been widely used for the study of diet-induced obesity, diabetes, and atherosclerosis (28).…”

mentioning

confidence: 99%

Hepatic overexpression of SIRT1 in mice attenuates endoplasmic reticulum stress and insulin resistance in the liver

et al. 2011

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Endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of human type 2 diabetes (T2DM). Although SIRT1 has a therapeutic effect on metabolic deterioration in T2DM, the precise mechanisms by which SIRT1 improves insulin resistance remain unclear. Here, we demonstrate that adenovirus-mediated overexpression of SIRT1 in the liver of diet-induced insulin-resistant low-density lipoprotein receptor-deficient mice and of genetically obese ob/ob mice attenuates hepatic steatosis and ameliorates systemic insulin resistance. These beneficial effects were associated with decreased mammalian target of rapamycin complex 1 (mTORC1) activity, inhibited the unfolded protein response (UPR), and enhanced insulin receptor signaling in the liver, leading to decreased hepatic gluconeogenesis and improved glucose tolerance. The tunicamycin-induced splicing of X-box binding protein-1 and expression of GRP78 and CHOP were reduced by resveratrol in cultured cells in a SIRT1-dependent manner. Conversely, SIRT1-deficient mouse embryonic fibroblasts challenged with tunicamycin exhibited markedly increased mTORC1 activity and impaired ER homeostasi and insulin signaling. These effects were abolished by mTORC1 inhibition by rapamycin in human HepG2 cells. These studies indicate that SIRT1 serves as a negative regulator of UPR signaling in T2DM and that SIRT1 attenuates hepatic steatosis, ameliorates insulin resistance, and restores glucose homeostasis, largely through the inhibition of mTORC1 and ER stress.

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“…Microsomal triglyceride transfer protein (MTTP) deficient mice have reduced plasma triglycerides levels but develop hepatic steatosis without insulin resistance and inflammation [36]. Similarly, low-density lipoprotein receptor (LDLR) deficient mice also develop hepatic steatosis [37]. Thus, although we did not observe a decrease in plasma triglycerides, decreased expression of Mttp and Ldlr could be a major cause of the development of hepatic steatosis in mice fed formononetin and C7F.…”

Section: Discussionmentioning

confidence: 76%

2-Heptyl-Formononetin Increases Cholesterol and Induces Hepatic Steatosis in Mice

Andersen

Schjoldager

Tortzen

et al. 2013

BioMed Research International

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Consumption of isoflavones may prevent adiposity, hepatic steatosis, and dyslipidaemia. However, studies in the area are few and primarily with genistein. This study investigated the effects of formononetin and its synthetic analogue, 2-heptyl-formononetin (C7F), on lipid and cholesterol metabolism in C57BL/6J mice. The mice were fed a cholesterol-enriched diet for five weeks to induce hypercholesterolemia and were then fed either the cholesterol-enriched diet or the cholesterol-enriched diet-supplemented formononetin or C7F for three weeks. Body weight and composition, glucose homeostasis, and plasma lipids were compared. In another experiment, mice were fed the above diets for five weeks, and hepatic triglyceride accumulation and gene expression and histology of adipose tissue and liver were examined. Supplementation with C7F increased plasma HDL-cholesterol thereby increasing the plasma level of total cholesterol. Supplementation with formononetin did not affect plasma cholesterol but increased plasma triglycerides levels. Supplementation with formononetin and C7F induced hepatic steatosis. However, formononetin decreased markers of inflammation and liver injury. The development of hepatic steatosis was associated with deregulated expression of hepatic genes involved in lipid and lipoprotein metabolism. In conclusion, supplementation with formononetin and C7F to a cholesterol-enriched diet adversely affected lipid and lipoprotein metabolism in C57BL/6J mice.

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Differential response of two models of genetically modified mice fed with high fat and cholesterol diets: relationship to the study of non-alcoholic steatohepatitis

Cited by 13 publications

References 25 publications

Inhibition of Bone Morphogenetic Protein Signaling Reduces Vascular Calcification and Atherosclerosis

Inhibition of Bone Morphogenetic Protein Signaling Reduces Vascular Calcification and Atherosclerosis

Hepatic overexpression of SIRT1 in mice attenuates endoplasmic reticulum stress and insulin resistance in the liver

2-Heptyl-Formononetin Increases Cholesterol and Induces Hepatic Steatosis in Mice

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