Ghazi, Samira; (1999) Factors influencing expression of lecithin:cholesterol acylatrasferase. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In this thesis, the regulation and secretion of lecithin: cholesterol acyltransferase (LCAT), the plasma enzyme which esterifies lipoprotein cholesterol, has been studied including LCAT mRNA tissue distribution and developmental expression in the guinea pig. The relationship between lipoprotein production and LCAT synthesis, as measured by Northern blotting, was examined in HepG2 (human hepatoblastoma) cells, after enhancing secretion of triglyceride-rich VLDL by oleic acid supplementation, and in the intestine of fat-fed guinea-pigs. In HepG2 cells, oleic acid diminished LCAT mRNA, while guinea pig intestinal LCAT mRNA was unchanged. Apolipoprotein A1 (apo-A1) is the main LCAT co-factor and hence may influence LCAT expression. Their co-ordinate regulation was examined by altering production of apo-A1 in HepG2 cells and then measuring both LCAT and apo-A1 mRNA. Initially, HepG2 cells were pre-incubated with HDL to reduce their cholesterol content and suppress apo-A1 mRNA; when cholesterol levels were replenished, the rise in apo-A1 mRNA was accompanied by increased LCAT mRNA. Moreover, when apo-A1 expression was reduced by glucose deprivation, LCAT mRNA also fell even though the cells remained viable. However, when apo-A1 mRNA was increased by the hypolipidaemic drug, gemfibrozil, levels of LCAT mRNA fell. These findings suggest that, while hepatic LCAT mRNA is modulated by cellular lipid content and changes in lipoprotein production, there is no obvious co-ordinate regulation of LCAT and apo-A1 expression. LCAT mRNA was reduced more than mRNA of other secreted proteins (apo-A1, albumin and transferrin), in 5 liver biopsy specimens from jaundiced patients compared to normal liver. Similarly, exposing HepG2 cells to increasing amounts of different hepatotoxic agents, generally reduced LCAT mRNA before apo-A1 mRNA fell. A broadly similar conclusion was drawn from experiments in vivo when mice were administered hepatotoxins (galactosamine, lipopolysaccharide and the purine analogue, 4-APP). These various studies support the emerging concept that plasma LCAT activity is a sensitive marker of liver synthetic function and a reliable diagnostic indicator of liver damage in humans.

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