Unraveling the metabolic pattern of angiopoietin-like 3 knock-out mouse models under fasting and fed conditions

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): University of Milan Background Angiopoietin-like 3 (ANGPTL3) is a hepatokine and a regulator of lipid and lipoprotein metabolism through lipoprotein lipase and endothelial lipase inhibition, preventing the hydrolyzation of lipoprotein-derived triglycerides. A lack of ANGPTL3 results into a hypolipidemic phenotype, with a lower profile of lipids and lipoproteins, and this is evident in humans carrying a loss of function mutation, or in cellular or in vivo models. ANGPTL3 action, from the liver, is finely regulated between oxidative and storage tissues in the fasting and postprandial phases; from the current pharmacological treatments a possible ANGPTL3 intrahepatic role besides the lipases’ inhibition is emerging, thus possibly affecting the systemic metabolism with different implications. Purpose An axis between ANGPTL3 and other Angiopoietin-like proteins is known to regulate the triglyceride partitioning after a meal or during fasting, however the effect on tissues and the following metabolic and pathologic implications are still not known. Therefore, we aim to describe the impact of ANGPTL3 deficiency in fasting or in a postprandial state, and in different compartments of the organism. Methods As models, we utilized Angptl3 Knock-out (KO) mice (C57BL6/J background) and their littermate controls (wild-type, WT) fed a chow diet for 16 weeks. We assessed the metabolic phenotype with indirect calorimetry and with lipids, glucose, and insulin tolerance tests; we evaluated changes in plasma lipids under fast, fed, and fast-refeed settings and we investigated the histology of key metabolic organs. Results ANGPTL3 KO mice fed ad libitum a chow diet are hypolipidemic (plasma triglycerides levels: 42,42±8,80 mg/dL in ANGPTL3 KO mice vs. 122,02±55,09 mg/dL in WT mice; plasma cholesterol levels: 44,00±9,11 mg/dL in ANGPTL3 KO mice vs. 76,51±15,87 mg/dL in WT mice). The oral charge lipid challenge suggests that KO mice have lower lipid levels at all time points. Conclusions This preliminary profiling of ANGPTL3 KO mice under fasting and fed conditions highlights the hypolipidemia of these models, and the potentially beneficial impact of ANGPTL3 deficiency on their metabolism compared to controls.