OBJECTIVEIncreased plasma concentrations of apolipoprotein B100 often present in patients with insulin resistance and confer increased risk for the development of atherosclerosis. Naturally occurring polyphenolic compounds including flavonoids have antiatherogenic properties. The aim of the current study was to evaluate the effect of the polymethoxylated flavonoid nobiletin on lipoprotein secretion in cultured human hepatoma cells (HepG2) and in a mouse model of insulin resistance and atherosclerosis.RESEARCH DESIGN AND METHODSLipoprotein secretion was determined in HepG2 cells incubated with nobiletin or insulin. mRNA abundance was evaluated by quantitative real-time PCR, and Western blotting was used to demonstrate activation of cell signaling pathways. In LDL receptor–deficient mice (Ldlr−/−) fed a Western diet supplemented with nobiletin, metabolic parameters, gene expression, fatty acid oxidation, glucose homeostasis, and energy expenditure were documented. Atherosclerosis was quantitated by histological analysis.RESULTSIn HepG2 cells, activation of mitogen-activated protein kinase-extracellular signal–related kinase signaling by nobiletin or insulin increased LDLR and decreased MTP and DGAT1/2 mRNA, resulting in marked inhibition of apoB100 secretion. Nobiletin, unlike insulin, did not induce phosphorylation of the insulin receptor or insulin receptor substrate-1 and did not stimulate lipogenesis. In fat-fed Ldlr−/− mice, nobiletin attenuated dyslipidemia through a reduction in VLDL-triglyceride (TG) secretion. Nobiletin prevented hepatic TG accumulation, increased expression of Pgc1α and Cpt1α, and enhanced fatty acid β-oxidation. Nobiletin did not activate any peroxisome proliferator–activated receptor (PPAR), indicating that the metabolic effects were PPAR independent. Nobiletin increased hepatic and peripheral insulin sensitivity and glucose tolerance and dramatically attenuated atherosclerosis in the aortic sinus.CONCLUSIONSNobiletin provides insight into treatments for dyslipidemia and atherosclerosis associated with insulin-resistant states.

Study Type -Prevalence (retrospective cohort) Level of Evidence 2b BJUI B J U I N T E R N A T I O N A LWhat's known on the subject? and What does the study add? Shockwave lithotripsy is a common and effective treatment method for kidney stones, but has been associated with long-term complications, namely hypertension and diabetes. We compared the prevalence of these two disease in patients treated with lithotripsy to the background provincial population. Our analyses did not find an association between lithotripsy and the development of these diseases.Shockwave lithotripsy is an effective treatment modality for urolithiasis. The mechanism of stone communition during lithotripsy as well as the acute complications that occur following this treatment have been well described; however, the long-term consequences of this procedure have not been clearly defined. Diabetes and hypertension have been associated with lithotripsy at 19 years follow-up, though this relationship is controversial. This issue is further complicated by the interrelatedness of metabolic dysfunction and stone disease.Our data show that there is no association between lithotripsy and the development of either hypertension or diabetes. Patients treated for urolithiasis 20 years ago with shockwave lithotripsy were contacted, and their prevalence of diabetes and hypertension in these subjects was compared to the background population of British Columbia. The analysis also considered whether the properties of shockwaves delivered by the original Dornier HM-3 versus a modified Dornier HM-3 differentially affected the risk of our subjects developing these diseases. We did not find that lithotripsy, let alone the type of lithotriptor, was a risk factor for developing hypertension and diabetes. We postulate that the development of renal calculi in our subjects is more indicative of an overall metabolic syndrome where there is increasing evidence that patients with kidney stones get hypertension and diabetes and vice-versa. The development of these diseases is not related to shockwave lithotripsy, but rather to a systemic metabolic dysfunction. OBJECTIVES