Regulation and Pathology of Lipid Metabolism The Department of Biochemistry of Medical Faculty Presents now Regulation and Pathology of Lipid Metabolism Edited by Attila Sandor

Regulation and Pathology of Lipid Metabolism The fatty acid-glucose cycle Regulation of cholesterol synthesis at HMG-CoA reductase the inhibitory effect of cholesterol by covalent modification (-P) at the level of gene expression Regulation of ketogenesis at HMG-CoA synthase by succinylation changed gene expression Regulation of fatty acid synthesis at acetyl-CoA carboxylase Pathological lipid metabolism Tay-Sachs disease Propionemia, methylmalonemia Familial hypercholesterolemia Author`s picture

Combined inhibititory effect of ATP and citrate on the PFK activity Reg. in Metab. by Newsholm, 1977

Author`s picture

The theory of glucose/fatty acid cycle The theory of the cycle states, if plasma Glc is decreased, fatty acids are mobilized from adipose tissues (fasting, effect of glucagon) and the increased fatty acid level will decrease Glc utilization, restoring Glc level and maintaining homeostasis in this way. Author`s picture

Regulation and Pathology of Lipid Metabolism The fatty acid-glucose cycle Regulation of cholesterol synthesis at HMG-CoA reductase the inhibitory effect of cholesterol by covalent modification (-P) at the level of gene expression Regulation of ketogenesis at HMG-CoA synthase by succinylation changed gene expression Regulation of fatty acid synthesis at acetyl-CoA carboxylase Pathological lipid metabolism Tay-Sachs disease Propionemia, methylmalonemia Familial hypercholesterolemia Author`s picture

HMG-CoA is a branchpoint Cholesterol Reductase HMG-CoA synthase Cleavage enzyme Ketone bodies

HMG-CoA reductase is the regulated enzyme on the way to cholesterol synthesis HMG-CoA Phosphorylation by AMPK Cholesterol Insulin Gene Expression Glucagon Drugs (Statins)

AMP dependent Protein Kinase Authors`picture

Regulation and Pathology of Lipid Metabolism The fatty acid-glucose cycle Regulation of cholesterol synthesis at HMG-CoA reductase the inhibitory effect of cholesterol by covalent modification (-P) at the level of gene expression Regulation of ketogenesis at HMG-CoA synthase by succinylation changed gene expression Regulation of fatty acid synthesis at acetyl-CoA carboxylase Pathological lipid metabolism Tay-Sachs disease Propionemia, methylmalonemia Familial hypercholesterolemia Author`s picture

HMG-CoA synthase is regulatorory for ketone body synthesis

Regulation of ketone body synthesis trough the HMG-CoA synthase Acetoacetyl-CoA Acetyl-CoA HMG-CoA synthase Acetyl-CoA Succinyl-CoA HMG-CoA The liver contains two HMG-CoA synthases, one cytosolic for cholesterol synthesis and an other mitochondrial rate limiting for for ketone body synthesis. The latter undergoes a short term covalent modification via succinylation/desuccinylation of pre-existing enzyme. This presents a rare way of covalent modification of an enzyme.

Regulation and Pathology of Lipid Metabolism The fatty acid-glucose cycle Regulation of cholesterol synthesis at HMG-CoA reductase the inhibitory effect of cholesterol by covalent modification (-P) at the level of gene expression Regulation of ketogenesis at HMG-CoA synthase by succinylation changed gene expression Regulation of fatty acid synthesis at acetyl-CoA carboxylase Pathological lipid metabolism Tay-Sachs disease Propionemia, methylmalonemia Familial hypercholesterolemia Author`s picture

Regulation of acetyl-CoA carboxylase (ACC) CH3-COSCoA COO-CH3-COSCoA ACC CO2-Biotin acetyl-CoA malonyl-CoA Glucagon Insulin ACC, the 2nd and ATP-citrate lyase, the1st lipogenic enzymes are regulated by an inhibiting phosphorylation Stryer,5th ed. 22.26, p.625

Regulation and Pathology of Lipid Metabolism The fatty acid-glucose cycle Regulation of cholesterol synthesis at HMG-CoA reductase the inhibitory effect of cholesterol by covalent modification (-P) at the level of gene expression Regulation of ketogenesis at HMG-CoA synthase by succinylation changed gene expression Regulation of fatty acid synthesis at acetyl-CoA carboxylase Pathological lipid metabolism Tay-Sachs disease Propionemia, methylmalonemia Familial hypercholesterolemia Author`s picture

Genetic diseasis in connection to fatty acid oxidation propionemia methylmalonyl-uria member of citric acid cycle Lehn.,4th ed.17-11 p.642

Regulation and Pathology of Lipid Metabolism The fatty acid-glucose cycle Regulation of cholesterol synthesis at HMG-CoA reductase the inhibitory effect of cholesterol by covalent modification (-P) at the level of gene expression Regulation of ketogenesis at HMG-CoA synthase by succinylation changed gene expression Regulation of fatty acid synthesis at acetyl-CoA carboxylase Pathological lipid metabolism Tay-Sachs disease Propionemia, methylmalonemia Familial hypercholesterolemia Author`s picture

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