Abstract
BackgroundCholesterol accumulation causes pancreatic beta cell lipotoxicity and dysfunction. Cholesteryl ester transfer protein (CETP) plays an important role in blood lipid homeostasis. However, its role in tissue lipid metabolism remains unclear. We hypothesized that plasma CETP impact cholesterol homeostasis in the beta cells, thus damaging their functions.MethodsThe adipose tissue-specific CETP expression transgenic (aP2-CETPTg) mice, characterized by high CETP levels in the circulation, were used in this study. Pancreatic islet cholesterol and beta cell function were assessed in mice. We further measured mRNA levels of the genes involved in beta cell proliferation and differentiation, inflammation and cholesterol metabolism. TUNEL assay was applied to investigate beta cell apoptosis in islets.ResultsThe aP2-CETPTg mice exhibited glucose intolerance, lower plasma insulin concentrations but increased insulin sensitivity compared with wild type mice. In addition, glucose-stimulated insulin secretion from isolated pancreatic islets significantly decreased, and free cholesterol significantly increased. Moreover, the number and size of islets from aP2-CETPTg mice were significantly decreased. Genes involved in beta cell proliferation, such as Pdx1 and BETA2, were down-regulated; genes involved in inflammation and ER stress, such as IL-1β, CHOP, and Xbp1 were up-regulated, in line with an increase of beta cell apoptosis.ConclusionsPlasma CETP causes free cholesterol accumulation in islets which could contribute to beta cell dysfunction. Thus, CETP inhibition could be a novel protective strategy for dyslipidemia related to diabetes and obese.
Highlights
Cholesterol accumulation causes pancreatic beta cell lipotoxicity and dysfunction
AP2-CETPTg mice exhibit impaired glucose tolerance and insulin secretion To study the effects of Cholesteryl ester transfer protein (CETP) on systemic glucose metabolism and insulin secretion in NFR-CETPTg and aP2CETPTg mice, we conducted Intraperitoneal glucose tolerance test (IPGTT), Intraperitoneal insulin tolerance test (IPITT) in vivo
We found that NFR-CETPTg and aP2-CETPTg mice had an increased sensitivity to insulin compared with WT mice (Fig. 3b)
Summary
Cholesteryl ester transfer protein (CETP) plays an important role in blood lipid homeostasis. We hypothesized that plasma CETP impact cholesterol homeostasis in the beta cells, damaging their functions. Islet beta cell dysfunction and insulin resistance are major characteristics of pathophysiology of T2DM. We speculated that circulating CETP may mediate cholesterol homeostasis in islet beta cells. Most clinical studies have shown that CETP mass was increased in patients with T2DM and obesity [10]. Our previous study showed that glucose uptake and intracellular cholesterol were increased when 3T3-L1 adipocyte was transfected with CETP [14]. All these studies indicated that CETP might play a role in glucose metabolism
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