Metabolic: lecture 28

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Questions and Answers

What is the primary effect of insulin on HMG-CoA reductase activity?

Reduces enzyme synthesis in the nucleus

Decreases activity through proteolytic degradation

Increases activity through dephosphorylation (correct)

Increases phosphorylation of the enzyme

How does SREBP regulate cholesterol metabolism when sterol levels decline?

High levels of sterol induce SREBP degradation

SREBP remains in the ER with Insig and SCAP

Insig promotes the phosphorylation of SREBP

SREBP is cleaved and activates HMG-CoA reductase transcription (correct)

What triggers the degradation of HMG-CoA reductase by proteasomes?

Binding of AMPK to the enzyme

Phosphorylation by glucagon

Ubiquitination initiated by Insig binding to oxysterol (correct)

Inhibition by malonyl-CoA

Which statement about AMPK is true?

AMPK is a sensor that responds to energy levels Signup and view all the answers

What effect does metformin have on AMPK?

It activates AMPK by inhibiting mitochondrial respiratory chain Signup and view all the answers

What molecule is the precursor to triacylglycerols (TAGs) and phospholipids?

Phosphatidic acid Signup and view all the answers

What is the role of HMG-CoA reductase in cholesterol biosynthesis?

It reduces hydroxymethylglutaryl-CoA to mevalonate. Signup and view all the answers

Which metabolite is formed when phosphatidic acid undergoes the action of lipin?

1,2-diacylglycerol Signup and view all the answers

What structural feature distinguishes steroids from other lipid types?

Four-ring structure Signup and view all the answers

How do statin drugs function in cholesterol regulation?

By competitive inhibition of HMG-CoA reductase. Signup and view all the answers

Which factor positively regulates HMG-CoA reductase activity?

Dephosphorylation Signup and view all the answers

What is the first step in the process of eukaryotic cholesterol biosynthesis?

Condensation of three acetates to form mevalonate. Signup and view all the answers

Which regulatory mechanism does NOT affect HMG-CoA reductase?

Competitive inhibition by fatty acids Signup and view all the answers

What occurs when sterol levels decline in relation to SREBP?

The SCAP/SREBP complex moves to the Golgi for cleavage. Signup and view all the answers

What role does Insig play in the regulation of HMG-CoA reductase?

Insig triggers the ubiquitination and degradation of HMG-CoA reductase. Signup and view all the answers

What happens to SREBP when sterol levels are high?

SREBP is retained in the ER along with SCAP and Insig. Signup and view all the answers

Which statement accurately describes the function of HMG-CoA reductase?

It catalyzes the conversion of HMG-CoA into mevalonate. Signup and view all the answers

Which condition leads to the proteolytic degradation of HMG-CoA reductase?

Binding of Insig to oxysterol. Signup and view all the answers

Study Notes

Course Information

Final exam: Tuesday, December 10th, 8:30 AM - 10:30 AM in THRN 1307
Course review: Friday, December 6th

Lipid Synthesis

Two types of lipids stored in the body: triglycerides and cholesterol
Synthesis of triglycerides (TAGs): begins with phosphatidic acid (PA) from glycerol-3-phosphate (G3P). Fatty acids are then attached to the glycerol backbone by acyltransferases, releasing CoA. TAGs consist of 3 fatty acids and glycerol

Cholesterol, Steroids, and Isoprenes

Chemically related; all originate from isoprene units
Distinct from triglycerides, phospholipids, and sphingolipids
Built on biosynthesis using a 5-carbon isoprene unit

Overview of Eukaryotic Cholesterol Biosynthesis

Three acetyl-CoA condense to form mevalonate
Mevalonate is converted to a phosphorylated 5-carbon isoprene
Six isoprenes polymerize to form the 30-carbon linear squalene
Squalene cyclizes to form the four rings that are modified to produce cholesterol

Formation of Mevalonate from Acetyl-CoA

Three acetyl-CoA molecules condense to form hydroxymethylglutaryl-CoA (HMG-CoA)
HMG-CoA is reduced to form mevalonate
HMG-CoA reductase is a common target for cholesterol-lowering drugs

Steroid Hormones Derived from Cholesterol

Cholesterol is a precursor to various hormones
Cortisol (glucocorticoid) affects protein and carbohydrate metabolism, and suppresses the immune response
Corticosterone (mineralocorticoid) regulates the absorption of sodium, chloride and bicarbonate in the kidney
Testosterone and estradiol are male and female sex hormones, respectively influencing secondary sexual characteristics and regulating reproductive cycles

Statin Drugs Inhibit HMG-CoA Reductase

Statins resemble mevalonate, which are competitive inhibitors of HMG-CoA reductase
First statin, lovastatin, was found in fungi
Statins lower serum cholesterol by a significant percentage
Statins lower cholesterol biosynthesis, since, cholesterol is a precursor for some hormones

Modes of Regulation of Cholesterol Synthesis

Covalent modification of HMG-CoA reductase
Transcriptional regulation of HMG-CoA reductase gene
Proteolytic degradation of HMG-CoA reductase

AMP-activated protein kinase (AMPK) in the regulation of cholesterol

AMP-activated protein kinase (AMPK) inactivates HMG-CoA reductase when AMP/ATP ratio rises.
In response to low energy and high AMP levels, AMPK is activated, leading to the phosphorylation and inactivation of HMG-CoA reductase. This results in decreased cholesterol synthesis
Glucagon and epinephrine signaling lead to a cascade that results in the activation of AMPK by phosphorylation and subsequent cholesterol synthesis reduction. Conversely, insulin promotes glycogen synthesis and increases insulin sensitivity, leading to de-phosphorylation. This results in AMPK inactivation and activation of cholesterol synthesis.
AMP-dependent protein kinase (AMPK) is activated when AMP levels rise and phosphorylates HMG-CoA reductase, thereby reducing its activity and decreasing cholesterol synthesis. Glucagon and epinephrine signaling increase AMPK activity through phosphorylation. Insulin signaling promotes the dephosphorylation of AMPK, increasing activity and thus, cholesterol.

Regulation of HMG-CoA Reductase by Proteolytic Degradation

Insig (insulin-induced gene protein) senses cholesterol levels. When cholesterol levels are high, Insig binds oxysterols, triggering ubiquitination of HMG-CoA reductase. This targets the enzyme for degradation by proteasomes.

Regulation of Cholesterol Metabolism

Acetyl-CoA is converted to β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) and subsequently to mevalonate
The synthesis of mevalonate can be regulated by hormones such as insulin (stimulates) and glucagon/epinephrine (inhibits)

Fatty Acid Metabolism

AMPK inhibits acetyl-CoA carboxylase (ACC), reducing malonyl-CoA levels, and this removes the inhibition of fatty acid oxidation.
This allows for a faster rate of fatty acid oxidation when energy demands are high.

AMPK as a global regulator of energy metabolism

AMPK is an energy sensor; its activity increases when ATP levels decrease and AMP levels increase
AMPK regulates diverse metabolic pathways, including fatty acid synthesis, cholesterol synthesis, glycogen synthesis, and protein synthesis
AMPK is a global metabolic regulator
Its activity is regulated by factors responsive to ATP levels, exercise, hormones (e.g. insulin, glucagon) and other physiological signals

AMPK as a target for treatment of type II diabetes

Metformin inhibits mitochondrial respiratory chain complex I and activates AMPK. Elevated AMPK signaling leads to increased fatty acid oxidation, reduced hepatic glucose production, decreased cholesterol synthesis and improved insulin sensitivity.

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Description

This quiz covers the synthesis pathways of lipids, focusing on triglycerides and cholesterol. It includes details on how triglycerides are formed from phosphatidic acid and the biosynthesis of cholesterol from acetyl-CoA. Test your understanding of these crucial metabolic processes.