BASIC deficiency disrupts hepatic metabolism and pancreatic α-cell function during fasting

RWTH Publications (RWTH Aachen)

Abstract

In this study, we have identified bile acid-sensitive ion channel (BASIC) expression in pancreatic α-cells of mice. Loss of BASIC significantly reduces the proportion of α-cells in the pancreatic islets, leading to a decrease in islet size and morphological alterations. Additionally, the mRNA expression of glucagon in islet tissue is markedly reduced in BASIC-/- mice. Histological analysis revealed that in both adult BASIC+/+ and BASIC-/- mice, there were no abnormalities in the proliferation or apoptosis of pancreatic islet cells (α-, β-, or δ-cells). However, in newborn BASIC-/- mice, α-cells proliferation appeared normal, but apoptotic activity was abnormally elevated, as indicated by increased cleaved-caspase 3 expression. Furthermore, the transcription factor PAX6, which promotes α-cells proliferation, was significantly downregulated in the islets of adult BASIC-/- mice. Correspondingly, serum glucagon levels were significantly lower in adult BASIC-/- mice compared to BASIC+/+ mice. Functional assays demonstrated that BASIC-/- islets exhibited impaired glucagon secretion, with freshly isolated BASIC-/- islets failing to distinguish between high (16 mM) and low (1 mM) glucose concentrations, maintaining consistently lower glucagon secretion compared to BASIC+/+ islets. Immunofluorescence and RT-PCR confirmed BASIC expression in the murine α-cells line (TC1 clone 6, TC1.6). Pharmacological modulation of BASIC further supported its role in α-cells proliferation and glucagon secretion, as inhibition of BASIC with Diminazene for 72 hours reduced proliferation, while activation with TUDCA significantly enhanced proliferation. Similarly, TUDCA enhanced glucagon secretion from TC1.6 cells under 1 mM glucose stimulation, whereas Diminazene abolished this effect. Moreover, BASIC expression was significantly upregulated after 24 hours of fasting in mice. In BASIC-deficient hepatocytes, a 6-hour in vitro fasting treatment led to a marked reduction in the key gluconeogenic enzyme PCK1, accompanied by abnormally increased fatty acid synthase (FASN) expression.

Authors 1

1. J. Yang corresponding Aachen

   RWTH Aachen University

   Affiliation as printed

   RWTH Aachen