Cholesterol accumulation and diabetes in pancreatic β-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity

Abstract

To determine the role of cholesterol synthesis in pancreatic b-cells, a transgenic model of in vivo activation of sterol-regulatory element binding protein 2 (SREBP-2) specifically in b-cells (TgRIP-SREBP-2) was developed and analyzed. Expression of nuclear human SREBP-2 in b-cells resulted in severe diabetes as evidenced by greater than 5-fold elevations in glycohemoglobin compared with C57BL/6 controls. Diabetes in TgRIP-SREBP-2 mice was primarily due to defects in glucose-and potassium-stimulated insulin secretion as determined by glucose tolerance test. Isolated islets of TgSREBP-2 mice were fewer in number, smaller, deformed, and had decreased insulin content. SREBP-2-expressing islets also contained increased esterified cholesterol and unchanged triglycerides with reduced ATP levels. Consistently, these islets exhibited elevated expression of HMG-CoA synthase and reductase and LDL receptor, with suppression of endogenous SREBPs. Genes involved in b-cell differentiation, such as PDX1 and BETA2, were suppressed, explaining loss of b-cell mass, whereas IRS2 expression was not affected. These phenotypes were dependent on the transgene expression. Taken Sterol-regulatory element binding protein 1c (SREBP-1c) is a membrane-bound transcription factor of the basic HLH (bHLH) leucine zipper family and has been established as a nutritional regulator of lipogenic enzymes in the liver (3, 4). Expression of SREBP-1c is highly upregulated by dietary intake of carbohydrates, sugars, and saturated FAs, whereas PUFAs, such as eicosapentaenoic acid, have been shown to inhibit hepatic SREBP-1c through multiple mechanisms (5, 6). These nutritional regulations of SREBP-1c are also observed in a cultured b-cell line and in isolated islets of mice (7,8). SREBP-1c also plays a role in insulin signaling by inhibiting insulin receptor substrate 2 (IRS-2), the major insulin-signaling mediator in the liver and in b-cells (9, 10).As a model for lipotoxicity by endogenous FAs in pancreatic b-cells, we previously developed transgenic mice overexpressing the active form of SREBP-1c under the insulin promoter expression (10). These mice exhibited impaired glucose tolerance in vivo due to both decreased b-cell mass and impaired insulin secretion estimated in isolated islets, which was enhanced by feeding the mice a high-fat, high-sucrose diet. The SREBP-1c-overexpressing islets had ATP depletion caused by enhanced lipogenesis and increased uncoupling protein 2 (UCP-2). Explaining the loss of b-cell mass, these islets had decreased expression of IRS-2 and PDX1. In addition to inhibition of GSIS,

Chronic exposure to leucine in vitro induces β-cell dysfunction in INS-1E cells and mouse islets

“…The principal targets for phosphorylation by AMPK are Hmgcr and Acaca (Towler & Hardie 2007). Interestingly, Srebf2 gene is tightly associated with the regulation of a number of genes encoding for enzymes involved in the CH biosynthetic pathway (Ishikawa et al 2008). Our RT-PCR results showed that leucine upregulated expressions of CH biosynthetic enzymes, e.g.…”

Distinct pathways of cholesterol biosynthesis impact on insulin secretion

“…This negative effect on b-cell function due to accumulation of cholesterol has also been shown in the overactivation of its sources. SREBP2 regulates the expression of HMG-CoA reductase and LDL receptor, and its overexpression increases cholesterol content, compromising islet morphology and GSIS in mouse islets (Ishikawa et al 2008). Thus, not only cholesterol reduction but also a dramatic increase in cholesterol content has been shown to reduce insulin secretion (Kruit et al 2011, Souza et al 2013.…”

Utility of the Triglyceride Level for Predicting Incident Diabetes Mellitus According to the Fasting Status and Body Mass Index Category: The Ibaraki Prefectural Health Study

“…Among these parameters, triglycerides (TG), which are particularly influenced by insulin resistance 6) , represent an independent risk factor for DM [7][8][9][10][11][12][13][14][15] . Lipotoxicity, which results from the accumulation of lipids in the skeletal muscle, liver and pancreas, plays an important role in the onset of insulin resistance and β-cell damage 16,17) . Although current guidelines recommend measuring the lipid levels in a fasting state, recent studies suggest that non-fasting lipid profiles may be useful in the clinical setting 18) .…”