Citrus Changshan Huyou extracts as natural GLP-1R agonists attenuate atherosclerosis via the GLP-1R/PKA/CREB pathway:...

Atherosclerosis (AS)-triggered cardiovascular diseases constitute a major global public health crisis. The pathological progression of AS is characterized by abnormal lipid accumulation, inflammatory cell infiltration and atherosclerotic plaque buildup in arterial walls. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are well known for hypoglycemic effects, and accumulating evidence proves they exert extra cardiovascular protective effects. This research aimed to explore whether Citrus Changshan Huyou extracts (HY) function as natural food-origin GLP-1RAs and further verify their anti-atherosclerotic activity and underlying mechanisms.

A GLP-1R-targeted cell screening model was adopted to detect the GLP-1 agonistic activity and cytotoxicity of HY in vitro. The five major flavonoid monomers of HY (eriocitrin, neoeriocitrin, narirutin, naringin and neohesperidin) were isolated and individually validated for GLP-1R activating capacity at the cellular level. A high-fat diet-induced ApoE^-/^- mouse model was established to assess the in vivo efficacy and biosafety of HY. Subsequent mechanistic experiments were conducted to clarify the regulatory role of HY on the intestinal GLP-1R/PKA/CREB signaling cascade and downstream vascular aging and inflammatory responses.

Cellular assays confirmed that HY possessed prominent GLP-1R agonistic activity with negligible cytotoxicity, and all five intrinsic flavonoid components of HY independently activated GLP-1R. In animal experiments, HY intervention markedly relieved excessive weight gain, corrected disordered blood lipid levels and shrank atherosclerotic plaque lesions in the aorta, without any detectable toxic reactions. Mechanistically, HY activated intestinal GLP-1R/PKA/CREB signaling, which further suppressed the expression of vascular senescence-associated proteins and alleviated inflammatory infiltration in aortic tissues.

This study verifies that HY is a safe and potent natural GLP-1RA derived from edible citrus raw materials with robust anti-atherosclerotic performance. The intestinal GLP-1R/PKA/CREB pathway mediates the dual protective effects of HY against vascular senescence and aortic inflammation. Our findings provide solid experimental support for the development of novel cardiovascular-protective functional food raw materials based on Changshan Huyou extracts.