Introduction and Objective: Pemvidutide is a long-acting, peptide-based GLP-1/glucagon dual receptor agonist that elicits significant reductions in body weight and serum lipids in preclinical and clinical studies. Reverse cholesterol transport (RCT) is an important process for removing excess cholesterol from peripheral tissues. Preclinical studies have suggested that glucagon may enhance the elimination of cholesterol, possibly due to enhanced RCT. Here, we investigated the effects of pemvidutide on RCT via cholesterol excretion in a preclinical model.Methods: Obese male Golden Syrian hamsters were treated daily with pemvidutide or vehicle for 35 days. On Day 35, macrophages labelled with 3H-cholesterol were injected intraperitoneally, and the appearance of the 3H-cholesterol in plasma, liver, and feces was quantitated over 72 hours. In an independent study, changes in the hepatic expression of genes involved in cholesterol transport were measured by reverse transcription-polymerase chain reaction (RT-PCR) following pemvidutide treatment.Results: Pemvidutide treatment significantly reduced total plasma triglycerides, total cholesterol, and LDL-cholesterol as compared to vehicle controls. Specifically, pemvidutide significantly reduced plasma 3H-cholesterol and increased the excretion of 3H-cholesterol and its metabolites in feces over 72 hours. RT-PCR analysis showed significantly increased hepatic gene expression of the cholesterol transporters ABCG5 and ABCG8 in the pemvidutide treated group compared to vehicle.Conclusion: Pemvidutide treatment increased excretion of cholesterol into feces and upregulated transporters of cellular cholesterol in the liver, consistent with increased RCT. These findings suggest that in addition to other mechanisms, pemvidutide improves serum cholesterol through enhanced cholesterol excretion.
M. Lucca Andrade: Employee; Altimmune Inc. J.J. Suschak: Employee; Altimmune Inc. B. Georges: Employee; Altimmune Inc. F. Briand: Employee; PHYSIOGENEX. Stock/Shareholder; PHYSIOGENEX. M.S. Roberts: Employee; Altimmune Inc.
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