Cholic Acid Enhances Visceral Adiposity, Atherosclerosis and Nonalcoholic Fatty Liver Disease in Microminipigs

Aim: We have recently established a novel swine model for studies of atherosclerosis using Microminipigs™ (µMPs) fed a high-fat/high-cholesterol diet (HcD). Using this swine model, we re-evaluated the effects of dietary cholic acid (CA) on serum lipid profile, atherosclerosis and hepatic injuries. Methods: The µMPs were fed HcD supplemented with 0.7% CA (HcD+CA) for eight weeks, and the effect of CA on serum lipoprotein levels, expression of oxidative stress markers, adiposity and lesion formation in the aorta, liver, and other organs was investigated. Results: The HcD+CA-fed group exhibited more visceral adiposity, progression of atherosclerosis and higher serum levels of oxidative stress markers than the HcD-fed group, even though they showed similar serum lipid levels. The liver demonstrated increased lipid accumulation, higher expression of oxidative stress markers, accelerated activation of foamy Kupffer cells and stellate cells, and increased hepatocyte apoptosis, indicating non-alcoholic fatty liver disease (NAFLD). Intriguingly, foamy macrophage mobilization was observed in various organs, including the reticuloendothelial system, pulmonary capillary vessels and skin very often in HcD+CA-fed µMPs. Conclusion: To our knowledge, this is the first large animal model, in which visceral obesity, NAFLD and atherosclerosis are concomitantly induced by dietary manipulation. These data suggest the detrimental effects of CA, potentially through local and systemic activation of oxidative stress-induced signaling to macrophage mobilization, on the acceleration of visceral adiposity, atherosclerosis and NAFLD.