Diet induced atherogenic hyperlipoproteinaemia and liver injury in cynomolgus macaques

This study was conducted to determine the efficacy of an experimental anti-atherosclerosis drug in the adult male cynomolgus monkey. A semipurified diet containing 0.5% cholesterol and 25.5% butter was fed to groups of 20, each, drug and placebo-treated animals for 18 months. Similar liver and arterial changes were present in both groups. However, we report here tissue changes seen in animals given placebo only, with plasma lipid and lipoprotein values of placebo-treated animals compared to those in animals fed nonatherogenic commercial ration. Animals fed atherogenic diet had enlarged livers (mean 3.9% b.w.), and all had evidence of hepatocellular lipid accumulation which was often marked and diffuse. Cholangitis was common including mononuclear cell infiltration, bile ductule proliferation and portal tract fibrosis. Five animals had severe portal fibrosis with bands of connective tissue extending into and around lobules (bridging fibrosis). All animals fed atherogenic diet developed hypercholesterolemia (greater than 600 mg/dl) which was the result of a three-fold increase in five cholesterol and cholesterol ester. Oleic acid was increased and linoleic acid was reduced in plasma phospholipids and cholesterol esters. Plasma lipoprotein distribution was altered with a marked increase in low density lipoproteins, increased very low density lipoproteins and decreased high density lipoproteins. These changes were undoubtedly caused by diet, i.e., high in cholesterol and saturated fat and limiting in linoleic acid. It is probable that diet-induced liver injury would affect the pathogenesis of atherosclerosis in this model since the liver is central in the synthesis and metabolism of lipoproteins.