56. Biochemistry - Lipid Metabolism III Regulation of TAG & F.A. Metabolism

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Questions and Answers

What is the primary location of acetyl-CoA carboxylase isoform ACC1 in humans?

Nucleus

Cell membrane

Cytoplasm (correct)

Mitochondria

Which of the following enzymes is inhibited by malonyl-CoA as a product of ACC2?

Fatty acid synthase

HMG-CoA reductase

Carnitine transferase I (CAT1) (correct)

Acetyl-CoA synthetase

What is the function of acetyl-CoA carboxylase isoform ACC2 in humans?

Regulation of long chain fatty acid oxidation (correct)

Promotion of fatty acid synthesis

Conversion of carbohydrates to fats

Inhibition of glucose oxidation

Which of the following best describes the structure of active acetyl-CoA carboxylase?

Long filaments Signup and view all the answers

What type of regulation does acetyl-CoA carboxylase undergo?

Both allosteric and hormonal regulation Signup and view all the answers

In terms of tissue distribution, which isoform of acetyl-CoA carboxylase is primarily found in lipogenic tissues?

ACC1 Signup and view all the answers

What is the relationship between acetyl-CoA and fatty acid metabolism?

Acetyl-CoA is central to both fatty acid synthesis and oxidation. Signup and view all the answers

How do the two isoforms of acetyl-CoA carboxylase typically exist in cells?

As homo-oligomers Signup and view all the answers

What is the mechanism by which glucagon favors gluconeogenesis in the liver?

Phosphorylates PFK-2, decreasing fructose-2,6-bisphosphate Signup and view all the answers

Which pathway is directly stimulated by insulin when blood glucose levels are high?

Glycolysis in the liver and TAG synthesis Signup and view all the answers

What role does fructose-2,6-bisphosphate (F26BP) play in the regulation of glycolysis and gluconeogenesis?

It serves as an allosteric inhibitor of fructose-bisphosphatase 1 Signup and view all the answers

How does the liver convert the glycerol backbone to glucose?

By gluconeogenesis Signup and view all the answers

What is the effect of phosphorylating glycogen synthase kinase 3 (GSK-3) on glycogenesis?

It activates glycogen synthase, facilitating glucose storage Signup and view all the answers

What is the role of glucagon in relation to hypoglycemia?

Promotes carbon flux to glucose Signup and view all the answers

What is the effect of dephosphorylation on acetyl-CoA carboxylase (ACC)?

It enhances the polymerization of ACC filaments. Signup and view all the answers

How does long chain fatty acid oxidation impact glucose metabolism in muscle?

Interferes with glucose metabolism by increasing acetyl-CoA Signup and view all the answers

Which molecule serves as an allosteric inhibitor of ACC when its concentration is sufficient?

Palmitoyl-CoA Signup and view all the answers

What effect does malonyl-CoA have on carnitine acetyltransferase I (CAT1)?

Inhibits CAT1 to enhance glucose metabolism Signup and view all the answers

How does epinephrine affect ACC activity in different tissues?

It increases cAMP levels, thereby activating PKA which inhibits ACC. Signup and view all the answers

What is a tissue-specific effect of ACC2 on CAT1?

Facilitates glucose clearance from the blood in muscle Signup and view all the answers

What role does insulin play in the regulation of ACC?

It activates Protein Phosphatase 1, favoring fatty acid synthesis. Signup and view all the answers

Which state of the body leads to ACC inactivity due to low concentration of citrate?

Catabolic state Signup and view all the answers

What happens to the citrate produced from acetyl-CoA in the mitochondria?

Exits the mitochondria and contributes to lipid synthesis Signup and view all the answers

Which of the following pathways is activated by epinephrine during hypoglycemia?

Glycogenolysis Signup and view all the answers

What triggers the release of insulin in the context of ACC activity regulation?

Hyperglycemia Signup and view all the answers

Which enzyme is primarily affected by the binding of citrate in the metabolic pathway?

Acetyl-CoA carboxylase Signup and view all the answers

What is the primary metabolic fate of acetyl-CoA derived from fatty acid catabolism?

Regeneration of 4-carbon organic acids for anabolic pathways Signup and view all the answers

What is the role of AMPK concerning ACC during energy-poor conditions?

AMPK phosphorylates ACC, shifting the balance to its inactive form. Signup and view all the answers

What effect does hypoglycemia have on ACC1/ACC2 activity?

Inhibits ACC2 to maintain glucose and ketone body production Signup and view all the answers

Which of the following statements about glucose metabolism in skeletal muscle is true?

Skeletal muscle is responsible for approximately 80% of insulin-stimulated glucose disposal Signup and view all the answers

How does the body respond to a fatty acid deficit concerning ACC activity?

ACC activity is favored despite low palmitoyl-CoA concentration. Signup and view all the answers

Which mechanism is primarily responsible for the inhibition of isocitrate dehydrogenase under high energy conditions?

Elevated concentrations of ATP and NADH Signup and view all the answers

What is the primary role of glycogen during hypoglycemic conditions?

Provide glucose rapidly through glycogenolysis Signup and view all the answers

What role does Acetyl-CoA play in the liver during hypoglycemia?

It promotes the synthesis of ketone bodies as an energy source. Signup and view all the answers

Which enzyme is NOT involved in the synthesis of acetoacetate in the liver?

b-hydroxybutyrate DH Signup and view all the answers

What happens to the carbon flux in hepatocytes when blood glucose levels are low?

It prioritizes gluconeogenesis over all other metabolic processes. Signup and view all the answers

Which statement regarding the liver's metabolism of ketone bodies is correct?

Liver lacks the enzyme to convert acetoacetate to acetoacetyl-CoA. Signup and view all the answers

What metabolic pathway is stimulated by glucagon in response to low blood glucose levels?

TAG mobilization from white adipose tissue. Signup and view all the answers

What determines the predominance of acetoacetate versus b-hydroxybutyrate in the body?

The NAD+/NADH ratio in the cytoplasm. Signup and view all the answers

How do ketone bodies affect glucose utilization in the brain?

They reduce glucose utilization while maintaining OAA levels. Signup and view all the answers

What is a preliminary diagnostic sign of massive ketone body production?

Signature odor of acetone in breath or urine. Signup and view all the answers

Which of the following statements about b-hydroxybutyrate DH is true?

It interconverts b-hydroxybutyrate and acetoacetate. Signup and view all the answers

Which enzyme is specifically absent in the liver that affects its ability to utilize ketone bodies?

Succinyl-CoA:acetoacetate CoA transferase Signup and view all the answers

Study Notes

Regulation of TAG & Fatty Acid Metabolism

Learning Objectives:
- Explain how acetyl-CoA carboxylase is regulated by metabolites and hormones.
- Explain the relevance of ketone bodies.
- List enzymes associated with ketone metabolism, their synthesis sites, and utilization sites.
- List effects of epinephrine/glucagon and insulin on carbohydrate and lipid metabolism.

Outline

I. Regulation of acetyl-CoA carboxylase:
- Acetyl-CoA carboxylase is regulated by metabolites and hormones.
II. Regulation of carnitine transferase I:
- Regulated by malonyl-CoA.
III. Fates of acetyl-CoA:
- Released from fatty acid oxidation.
IV. Ketone Bodies:
- Relationship between hypoglycemia and ketone bodies.
- Ketone body synthesis in the liver.
- Ketone body utilization by extrahepatic tissues.
V. Carbon Flux:
- Pathways stimulated by glucagon.
- Pathways stimulated by insulin.
VI. Appendices:
- Compare/contrast fatty acid synthesis and fatty acid oxidation.
- Resolve nomenclature of thiolase super-family of enzymes.

Regulation of Acetyl-CoA Carboxylase

Two major isoforms: ACC1 and ACC2
ACC1 predominant in lipogenic tissues: liver, adipose tissue, mammary gland
ACC2 predominant in skeletal and cardiac muscle
ACC2 associated with outer mitochondrial membrane, important in long-chain fatty acid oxidation
Malonyl-CoA, a potent inhibitor of carnitine shuttle (CAT1/CPT1).
ACC1/ACC2 exist as homo-oligomers (short protomers or long filaments)

Polymerization/Depolymerization

Regulated allosterically, by metabolite availability, and hormonally
Phosphorylation and/or palmitoyl-CoA binding promote depolymerization
Dephosphorylation and/or citrate binding promote polymerization.

Regulation by Hormones/metabolites

Epinephrine increases cAMP, activating protein kinase A (PKA), which phosphorylates ACC, leading to its inactive form
Glucagon has a similar effect in hepatocytes and adipocytes
Palmitoyl-CoA is an activator of AMPK, which phosphorylates ACC, and shifts toward an inactive form
Insulin activates protein phosphatase 1 (PP1), dephosphorylating ACC, and shifts toward an active form

Allosteric Control of ACC

Energy poor conditions (catabolism) favor isocitrate dehydrogenase activity, minimizing ACC activity.

Malonyl-CoA Inhibition of Carnitine Acetyltransferase I

Malonyl-CoA inhibits CAT I/CPT1 tissue-specifically, e.g., preventing futile cycle in liver/adipose tissue (synthesis of fatty acids)
In skeletal muscle, the inhibition of CAT1 by malonyl-CoA is linked to facilitating glucose clearance.

Fates of Acetyl-CoA

Condenses with oxaloacetate to create citrate, which can be oxidized in the TCA cycle.
Citrate exits mitochondria and can be used for lipid synthesis.
Acetyl-CoA can be used for amino acid synthesis, heme production, and glucose.
Acetyl-CoA is used by liver to produce ketone bodies as an alternate energy source during hypoglycemia.

Hypoglycemia-induced stimulation of gluconeogenesis

Liver shifts from lipid metabolism toward ketone body synthesis.
Acetyl-CoA accumulates in liver mitochondria, leading to ketone body synthesis.

Metabolic Pathways (Glucagon)

TAG mobilization in white adipose tissue
Glycogenolysis in liver via phosphorylation/activation of phosphorylase kinase.
Liver gluconeogenesis.

Metabolic Pathways (Insulin)

TAG uptake and storage in white adipose tissue
Glycogenesis in liver via phosphorylation inactivation of glycogen synthase kinase 3
Liver glycolysis via activation of PFK-2.

Appendices (Compare/contrast fatty acid synthesis and fatty acid oxidation)

Location (cytoplasm vs mitochondrial matrix)
Acyl group carriers (ACP vs CoA)
Metabolic intermediates (e.g., ACP, CoA, acyl-ACPs)
Catalytic reactions (e.g., enzymes in fatty acid synthesis vs fatty acid oxidation)
Steps (e.g, enzyme names in fatty acid synthesis vs fatty acid oxidation)

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Description

This quiz explores the regulation of key enzymes in fatty acid metabolism, such as acetyl-CoA carboxylase and carnitine transferase I. It covers the importance of ketone bodies, their synthesis and utilization, as well as the hormonal effects on metabolism. Test your understanding of these crucial biochemical pathways.