Lipoprotein Abnormalities in Galactosamine Hepatitis: A Model of Experimental Lecithin:Cholesterol Acyltransferase Deficiency

Abstract

D-galactosamine (GalN) produces, in the rat, an acute hepatitis, LCAT deficiency, and plasma lipoprotein abnormalities similar to those of human liver disease. Rats were sacrificed at intervals up to 24 h after a single ip injection of GalN, 750 mg/kg. No alpha band was found by plasma lipoprotein electrophoresis 12-24 h after GalN. Plasma LCAT activity was decreased 45% at 6 h and was < 10% of normal at 24 h. Cholesteryl esters decreased to 36% of total cholesterol at 12 h (control 70%) and at 24 h after GalN were only 15% of total cholesterol. Fractionation of plasma phospholipids at 24 h revealed lecithin increased to 68% of total phospholipid (control 46%), and lysolecithin decreased to 12% (control 25%). The increase of the lecithin/lysolecithin ratio to 5.6 after GalN (control 1.8) may reflect decreased LCAT activity. Arachidonyl esters accounted for only 9% of cholesteryl esters after GalN compared to 64% in controls. Lipoproteins were isolated by sequential ultracentrifugation: VLDL (d < 1.006); LDL, (1.006 <d < 1.05); LDL, (1.05 <d < 1.07); HDL (1.07 <d < 1.225). By electron microscopy VLDL were larger than normal, LDL, appeared as bilamellar vesicles or stacked discs, and LDL, and HDL as stacked bilamellar discs. Analysis 24 h after GalN disclosed most of the lipoproteins in the LDL fractions, and there was a 6-fold decrease in HDL. VLDL was relatively normal in lipid composition, but cholesteryl esters in LDL, were only 4% (control 22%)and phospholipids 68% (control 20%). Similar alterations in cholesteryl esters and phospholipids were found in LDL, and HDL. Thus GalN produces abnormalities in plasma lipids and lipoproteins which are strikingly similar to those of familial LC AT deficiency, providing a unique animal model to further investigate the role of LCAT in lipoprotein metabolism.

Key Words:

• apoproteins
• cholesterol
• cholesteryl esters
• high density lipoproteins (HDL)
• lecithin
• liver
• low density lipoproteins (LDL)
• lysolecithin
• phospholipids
• very low density lipoproteins (VLDL)