L-cell-specific Abca1 deficiency impairs glucose homeostasis through defective GLP-1 production in mice

Evidence suggests dietary cholesterol intake associates with higher diabetes risk, but mechanisms need further study. Glucagon-like peptide-1 (GLP-1), a glucose-regulating hormone produced by intestinal L-cells, has served as the basis for widely used diabetes therapeutics. However, how dietary cholesterol and intracellular cholesterol in L-cells affects GLP-1 and glucose regulation remains unclear. We studied ABCA1 (a cholesterol efflux protein) in L-cells using L cell specific Abca1 gene null nice (IntL-Abca1 ^-/- ) mice and ABCA1-targeted interventions in STC-1 and GLUTag cells. A high-cholesterol diet induced mouse glucose intolerance and reduced GLP-1. IntL-Abca1 ^-/- mice showed worse hyperglycemia and GLP-1 impairment via disrupted caveolin-1-β-catenin signaling. Abca1 overexpression and cholesterol depletion in STC-1 and GLUTag cells enhanced the CAV1-β-catenin pathway and GLP-1 secretion, whereas cholesterol loading, Abca1 siRNA knockdown, and treatment with probucol (an ABCA1 inhibitor) produced opposite effects. The findings of this study confirm that ABCA1 is a key regulator in maintaining cholesterol homeostasis in intestinal L cells and in the synthesis and secretion of GLP-1. Moreover, the regulatory effect of ABCA1 on GLP-1 is mediated through the CAV1-β-catenin signaling pathway. These observations further uncover promising therapeutic targets for metabolic disorders linked to diabetes.