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Investigation of the molecular mechanisms of the inhibition of hepatic fatty acid and cholesterol biosynthesis by hypolipidaemic agents

Hemingway, Cheryl Joy; (1997) Investigation of the molecular mechanisms of the inhibition of hepatic fatty acid and cholesterol biosynthesis by hypolipidaemic agents. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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The liver plays a central role in the production and metabolism of lipoproteins, with adipose tissue also contributing a large proportion of whole body fatty acid synthesis, in rat. Cholesterol and triacylglycerol are major lipid components of lipoproteins and inhibition of their hepatic synthesis is a major effect of many hypolipidaemic drugs in the treatment of atherosclerosis. The molecular mechanisms of inhibition of hepatic fatty acid and cholesterol biosynthesis by gemfibrozil and related hypolipidaemic agents and effects on general carbohydrate and lipid metabolism were investigated. Administration of the drug gemfibrozil (ip) produced a rapid (90 min) inhibition of fatty acid synthesis (68%) and cholesterol synthesis (81%) in rat liver in vivo. In primary rat hepatocyte cultures gemfibrozil and clofibrate were potent inhibitors of fatty acid synthesis, exhibiting maximal inhibition of 82% and 50%, respectively, with IC50 values of 0.6 mM and 1 mM, respectively. Similarly, gemfibrozil and clofibrate produced maximal inhibition of cholesterol synthesis of 90% and 68%, with IC50 values of 0.25 mM and 0.5 mM, respectively. Gemfibrozil and clofibrate have structures analogous to those of fatty acids. Another potent hypolipidaemic agent is MaxEPA which is composed largely of the fish oil n-3 eicosapentanoic acid (EPA). EPA and its parent compound linolenic acid produced 92% and 66% inhibitions of fatty acid synthesis in hepatocytes. Gemfibrozil stimulated the phosphorylation and inactivation of hepatic acetyl- CoA carboxylase (ACC), the regulatory enzyme of fatty acid synthesis, both in vivo and in hepatocytes. In vivo, gemfibrozil produced a 60% inhibition of HMG-CoA reductase activity in microsomes reducing 'total' activity by 30% and 'expressed' activity by 57%. This suggested the combination of phosphorylation and a decrease in enzyme concentration as the mechanism of inhibition. AMP-activated protein kinase (AMP-PK) phosphoiylates and inactivates both of these regulatory enzymes physiologically in liver. Gemfibrozil was observed to activate AMP-PK by 100 - 200% both in liver in vivo and in hepatocytes. Experiments with partially purified AMP-PK suggest that this activation is due to increased AMP-PK phosphorylation. Gemfibrozil clearly activates the AMP-PK cascade in rat liver. Gemfibrozil is known to stimulate fatty acid oxidation. This was confirmed by a 46% increase in circulating ketone bodies in gemfibrozil-treated rats in vivo and a 40% increase in ketone body production in hepatocytes treated with either gemfibrozil (1 mM) or clofibrate (5 mM). An additional mechanism in this partitioning of fatty acids away from esterification was demonstrated in vivo by a 58%> inhibition of hepatic glycerol-3-phosphate acyltransferase (GPAT). Phosphorylation and inactivation of GPAT by AMP-PK could not be demonstrated. Gemfibrozil treatment of rats for 150 min brought about a 15% rise in plasma glucose, a 14% rise in hepatic glycogen content and a 68% increase in the rate of hepatic glycogen synthesis. This indicated that decreased carbohydrate utilisation by liver in response to gemfibrozil requires compensatory measures by other pathways (and perhaps other tissues for example, white adipose tissue) and may have serious implications for gemfibrozil treatment of diabetic hyperlipidaemia.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Investigation of the molecular mechanisms of the inhibition of hepatic fatty acid and cholesterol biosynthesis by hypolipidaemic agents
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Acid; Biosynthesis; Cholesterol; Fatty; Hepatic; Hypolipidaemic; Inhibition
URI: https://discovery.ucl.ac.uk/id/eprint/10105007
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