Metabolic: lecture 28

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.

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.