Edited by Attila Sandor

The Department of Biochemistryof Medical Faculty

Presents now

Regulation and Pathology of Lipid Metabolism

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

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Combined inhibititory effect of ATP and citrate on the PFK activity

Reg. in Metab. by Newsholm, 1977

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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.

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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

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HMG-CoA is a branchpoint

Cleavage enzyme

Reductase

HMG-CoA synthase

Ketone bodies

Cholesterol

HMG-CoA reductase is the regulated enzyme on the way to cholesterol synthesis

Phosphorylation by AMPK

Drugs (Statins)

Cholesterol

Insulin

Glucagon

HMG-CoA

GeneExpression

AMP dependent Protein Kinase

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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

Acetyl-CoA

HMG-CoA

HMG-CoA synthase

Succinyl-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

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Regulation of acetyl-CoA carboxylase (ACC)

COO-CH3-COSCoAACC CO2-Biotin

CH3-COSCoA

acetyl-CoA malonyl-CoA

ACC, the 2nd and ATP-citrate lyase, the1st lipogenicenzymes are regulated by an inhibiting phosphorylation

Stryer,5th ed. 22.26, p.625

Insulin Glucagon

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

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member of citric acid cycle

Lehn.,4th ed.17-11 p.642

Genetic diseasis in connection to fatty acid oxidation

propionemia

methylmalonyl-uria

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

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Attila Sandor

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