Induction of apolipoprotein A-I gene expression by glucagon-like peptide-1 and exendin-4 in hepatocytes but not intestinal cells.

Objective: Diabetic dyslipidemia is an important risk factor for the development of macrovascular complications. Recent clinical trials suggest that diabetics treated with glucagon-like peptide-1 (GLP-1) have normalized lipid levels, including an increase in plasma high-density lipoprotein cholesterol (HDLc) levels.

Methods: To determine if GLP-1 (7-36 amide) and the GLP-1-like insulinotropic peptide exendin-4 regulate expression of apolipoprotein A-I (apo A-I), the primary anti-atherogenic component of high-density lipoprotein (HDL), HepG2 hepatocytes and Caco-2 intestinal cells, representative of tissues that express the majority of apo A-I, were treated with increasing amounts of each peptide and apo A-I gene expression was measured in the conditioned medium.

Results: Apo A-I secretion increased in both GLP-1 and exendin-4-treated HepG2, but not Caco-2 cells, and this was accompanied by similar changes in apo A-I mRNA levels and apo A-I promoter activity. Induction of apo A-I promoter activity by GLP-1 and exendin-4 required an SP1-responsive element. Hepatic ATP binding cassette protein A1 (ABCA1) expression, but not scavenger receptor class B type1 receptor expression was also induced by GLP-1 and exendin-4.

Conclusions: These results suggest that GLP-1- and exendin-4-mediated changes in HDLc are likely due to changes in hepatic expression of apo A-I and ABCA1.