FNH 350: Lipids - Lipid metabolism at fed and fasting state

what are the key organs involved in lipid regulation and why?

1. liver bc it’s the site of lipoprotein formation (VLDL and HDL) from endogenous lipids and apolipoproteins and site of formation of bile salts

2. adipose tissue bc it’s the site of fat storage

Which hormone regulates lipid metabolism in the fed state?

insulin

Describe liver lipid uptake during the fed state

• Triacylglycerol (TAG) formation and VLDL release:

  1. Chylomicron apoproteins (e.g., ApoB-48) interact with lipoprotein lipase and transfer FAs
     and MAGs to tissues

  2. After depletion to 20% of lipids, chylomicron remnants are taken up by the LIVER

  3. In the liver, FAs (not used for energy) are coupled to CoA before incorporated into TAG

  4. VLDL are formed with TAGs, apolipoproteins (ApoB-100), cholesterol, cholesterol ester
     and released of VLDL into blood

  5. ApoB-100 interacts with lipoprotein lipase (stimulated by insulin) on cell surface, FAs and
     MAGs taken up by peripheral tissues (intravascular hydrolysis: VLDL -> IDL -> LDL).

Describe lipid with glucose uptake in the liver during the fed state

• After high carbohydrate and lipid meals (e.g., poached salmon and jasmine rice):

  1. Insulin increases uptake of blood glucose by peripheral tissues

• Glucose-6-P in LIVER has the following fates

  1. Replenishing of glycogen stores (insulin stimulates glycogen synthesis)

  2. α-glycerol-3-phosphate (for formation of DAG+TAGs)

  3. G6P→ HMP shunt to provide NADPH for FA synthesis

  4. G6P → form acetyl-CoA -> formation of malonyl Co-A for endogenous
     synthesis of FAs

Cholesterol and CEs from chylomicron remnants (taken up by the liver) have the following possible fates:

1. Conversion to bile salts and secretion in the bile

2. Incorporation into VLDL and release into the blood stream

describe lipid uptake in adipose tissue during fed state

• Lipid metabolism:

  • Insulin stimulates lipoprotein lipase in adipocytes and presentation on cell surface:

    • hydrolysis of triacylglycerols in chylomicrons and VLDL

    • free fatty acids in adipocytes

    • free fatty acids, MAGs, and DAGs, are taken up by adipocytes and are re-esterified to triacylglycerols (storage of energy)

  • Insulin also inhibits hormone-sensitive lipase in adipocytes to prevent hydrolysis of stored TAGs (promotion of fat storage)

Describe lipid with glucose uptake in adipose during fed state

• After high carbohydrate and lipid meals (e.g., poached salmon
  and jasmine rice):

  1. Insulin increases uptake of blood glucose by peripheral tissues,
     including adipose tissue

• Glucose-6-P in ADIPOSE has the following fates:

  1. α-glycerol-3-phosphate (for formation of DAGs + TAGs)

  2. HMP shunt to provide NADPH for FA synthesis

  3. Form acetyl-CoA -> formation of malonyl Co-A for endogenous
     synthesis of FAs

Describe what happens in adipose tissue for lipid metabolism in post-absorptive/fasting state

• In post-absorptive and fasting states, glucagon and epinephrine signal change
  in lipid metabolism:

  1. Activation of the hormone-sensitive lipase (specific lipase in adipocytes)

  2. Hydrolysis of stored TAGs to fatty acids and glycerol

  3. Release of FAs bound to albumin into blood for hungry tissues (e.g., liver, muscle, etc.)

  4. Release of glycerol to the blood; can enter gluconeogenesis in the liver

How can adipose tissue use some of the fatty acids released from stored TAGs for its own energy?

Adipose tissue takes up less glucose and fatty acids during the post-absorptive state. Some of the fatty acids released from stored TAGs can undergo beta-oxidation to form acetyl-CoA, which enters the Krebs cycle and electron transport chain (ETC) to produce energy

What happens to lipid metabolism in post-absorptive state in liver tissue?

• Triacylglycerol formation – “Repackaging“

  1. FFAs released from adipose tissue are bound to albumin in circulation and are taken up
     by peripheral tissues, including liver

  2. Formation of TAGs in the liver

  3. Incorporation of TAGs into VLDL in the liver (lower rate compared to fed state)

• Fatty acid oxidation (mitochondria) = source of energy in the liver:

  1. Formation of acetyl-CoA via β-oxidation

  2. Acetyl-CoA enters TCA cycle - formation of CO2 and H2O; formation of ATP in electron
     transport chain

What is ketogenesis, and when does it occur?

Ketogenesis is the formation of ketone bodies in the liver. It occurs when acetyl-CoA accumulates because there are insufficient carbohydrates to provide precursors for TCA cycle intermediates and excess acetyl-CoA is produced from fatty acid breakdown.

It can occur during:

• Starvation.

• Consumption of a very low-carbohydrate diet.

• Usually uncontrolled type 1 diabetes, but also type 2 diabetes.

What are the ketone bodies, and how do they provide energy to other tissues?

The ketone bodies are acetoacetate, β-hydroxybutyrate, and acetone.

• Acetoacetate and β-hydroxybutyrate: Released into the blood and taken up by peripheral tissues, such as the brain, where they are converted into acetyl-CoA to enter the TCA cycle for energy production.

• Acetone: Also produced during ketogenesis and is a product for the liver to use

What is the purpose of ketogenesis, and how is a ketogenic diet used therapeutically?

Ketogenesis provides an alternative way for the liver to supply energy precursors to other tissues when carbohydrate availability is limited. Excess acetyl-CoA is converted into ketone bodies that can be transported through the blood.

A ketogenic diet is high in fat, adequate in protein, and low in carbohydrates. It can be used therapeutically to help reduce seizures in children with epilepsy