Potential therapeutic uses for ezetimibe beyond lowering LDL‐c to decrease cardiovascular events

Ahmed, Mohamed H.; Byrne, Christopher D.

doi:10.1111/j.1463-1326.2010.01261.x

Cited by 17 publications

(10 citation statements)

References 94 publications

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“…This is consistent with the SREBP pathway. Recent evidence suggests that NPC1L1 may affect transcription factors responsible for regulating insulin sensitivity and lipid metabolism (84). Several studies have shown that inhibition of NPC1L1 in rats significantly reduces cholesterol uptake, lowers weight gain, and decreases insulin resistance (85)(86)(87).…”

Section: Inflammation Decreases Benefits Of Diet Interventionsmentioning

confidence: 99%

Effects of Adiposity on Plasma Lipid Response to Reductions in Dietary Saturated Fatty Acids and Cholesterol

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Kris-Etherton

2011

Advances in Nutrition

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Dietary SFA and cholesterol are major targets for reducing plasma total and LDL cholesterol as a strategy to decrease cardiovascular disease risk. However, many studies show that excess adiposity attenuates the expected lipid and lipoprotein response to a plasma cholesterol-lowering diet. Diets low in SFA and cholesterol are less effective in improving the lipid profile in obese individuals and in patients with metabolic syndrome. In contrast, lean persons are more responsive to reductions in dietary SFA and cholesterol. Multiple mechanisms likely contribute to the altered plasma lipid responses to dietary changes in individuals with excess adiposity. The greater rate of hepatic cholesterol synthesis in obese individuals suppresses the expression of hepatic LDL receptors (LDLR), thereby reducing hepatic LDL uptake. Insulin resistance develops as a result of adipose-tissue induced inflammation, causing significant changes in enzymes necessary for normal lipid metabolism. In addition, the LDLR-mediated uptake in obesity is attenuated by alterations in neuroendocrine regulation of hormonal secretions (e.g. growth hormone, thyroid hormone, and cortisol) as well as the unique gut microbiota, the latter of which appears to affect lipid absorption. Reducing adipose tissue mass, especially from the abdominal region, is an effective strategy to improve the lipid response to dietary interventions by reducing inflammation, enhancing insulin sensitivity, and improving LDLR binding. Thus, normalizing adipose tissue mass is an important goal for maximizing the diet response to a plasma cholesterol-lowering diet.

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Section: Inflammation Decreases Benefits Of Diet Interventionsmentioning

confidence: 99%

Effects of Adiposity on Plasma Lipid Response to Reductions in Dietary Saturated Fatty Acids and Cholesterol

Flock

Green

Kris-Etherton

2011

Advances in Nutrition

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“…However, a recent survey estimated that 1/200 of the general population is heterozygous for familial hypercholesterolemia due to LDL receptor mutation, and a large proportion of these individuals failed to achieve recommended cholesterol levels upon statin therapy [17]. The advent of ezetimibe to block intestinal cholesterol absorption has provided an alternative strategy to reduce plasma cholesterol levels and decrease atherosclerosis risk [18]. The current study showing the effectiveness of Pla2g1b inactivation to reduce plasma cholesterol levels and suppress atherosclerosis in animals with LDL receptor deficiency suggests another novel strategy through Pla2g1b inhibition to enhance hepatic fatty acid oxidation for treatment of atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Group 1B phospholipase A2 inactivation suppresses atherosclerosis and metabolic diseases in LDL receptor-deficient mice

et al. 2014

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Objective Previous studies have shown that inactivation of the group 1B phospholipase A2 (Pla2g1b) suppresses diet-induced obesity, hyperglycemia, insulin resistance, and hyperlipidemia in C57BL/6 mice. A possible influence of Pla2g1b inactivation on atherosclerosis has not been addressed previously. The current study utilized LDL receptor-deficient (Ldlr−/−) mice with plasma lipid levels and distribution similar to hyperlipidemic human subjects as a preclinical animal model to test the effectiveness of Pla2g1b inactivation on atherosclerosis. Methods and Results The Pla2g1b+/+Ldlr−/− and Pla2g1b−/−Ldlr−/− mice were fed a low fat chow diet or a hypercaloric diet with 58.5 kcal% fat and 25 kcal% sucrose for 10 weeks. Minimal differences were observed between Pla2g1b+/+Ldlr−/− and Pla2g1b−/−Ldlr−/− mice when the animals were maintained on the low fat chow diet. However, when the animals were maintained on the hypercaloric diet, the Pla2g1+/+Ldlr−/− mice showed the expected body weight gain but the Pla2g1b−/−Ldlr−/− mice were resistant to diet-induced body weight gain. The Pla2g1b−/−Ldlr−/− mice also displayed lower fasting glucose, insulin, and plasma lipid levels compared to the Pla2g1b+/+Ldlr−/− mice, which displayed robust hyperglycemia, hyperinsulinemia, and hyperlipidemia in response to the hypercaloric diet. Importantly, atherosclerotic lesions in the aortic roots were also reduced 7-fold in the Pla2g1b−/−Ldlr−/− mice. Conclusion The effectiveness of Pla2g1b inactivation to suppress diet-induced body weight gain and reduces diabetes and atherosclerosis in LDL receptor-deficient mice suggest that pharmacological inhibition of Pla2g1b may be a viable strategy to decrease diet-induced obesity and the risk of diabetes and atherosclerosis in humans.

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“…Furthermore, low-carbohydrate diets increase the risk of both calcium and uric acid stones. 43,44 Therefore, it is possible to conclude that metabolic syndrome and treatment of metabolic syndrome are associated with an increase in risk of renal stone disease.…”

Section: Obesity and Renal Stone Disease And Cholesterol Gallstonesmentioning

confidence: 99%

The association between renal stone disease and cholesterol gallstones: the easy to believe and not hard to retrieve theory of the metabolic syndrome

2014

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(2014) The association between renal stone disease and cholesterol gallstones: the easy to believe and not hard to retrieve theory of the metabolic syndrome, Renal Failure, 36:6,[957][958][959][960][961][962] AbstractRenal stone disease and gallstone disease are widely prevalent and costly disease across the globe. Both renal stone disease and gallstone disease are associated with a variety of diseases including obesity, metabolic syndrome, dyslipidemia, hypertension, insulin resistance diabetes and gout. Importantly, the presence of either renal stone disease or gallstone disease is associated with an increased risk of cardiovascular disease. In a recent study of the Atherosclerosis Risk in Communities (ARIC), individuals with a history of gallstones were 54% more likely to report a history of nephrolithiasis after adjusting for age, gender, body size and other factors. Furthermore, in three large cohorts including over 240,000 subjects: the Nurses' Health Studies (NHS) I and II and the Health Professionals Follow-up Study (HPFS), showed that gallstone disease is independently associated with nephrolithiasis. The mechanisms linking gallstone disease and renal stone disease are complex and not yet established. Insulin resistance, lithogenic diets, alterations of transporters in gallbladder and urinary system, and pH are possible potential mechanisms for future exploration. How the liver communicates with kidney in individuals with renal stone disease and gallstone disease is not well known and whether this communication is similar as in hepto-renal syndrome is subject for future research. Further research is needed to determine: (i) the underlying mechanisms of renal stone disease and gallstone disease; (ii) the potential treatment of renal stone disease and gallstone disease.

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Potential therapeutic uses for ezetimibe beyond lowering LDL‐c to decrease cardiovascular events

Cited by 17 publications

References 94 publications

Effects of Adiposity on Plasma Lipid Response to Reductions in Dietary Saturated Fatty Acids and Cholesterol

Effects of Adiposity on Plasma Lipid Response to Reductions in Dietary Saturated Fatty Acids and Cholesterol

Group 1B phospholipase A2 inactivation suppresses atherosclerosis and metabolic diseases in LDL receptor-deficient mice

The association between renal stone disease and cholesterol gallstones: the easy to believe and not hard to retrieve theory of the metabolic syndrome

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