Regulation of Lipid Metabolism

REGULATION OF LIPID METABOLISM

LIPOLYSIS

  • Definition: Lipolysis is the breakdown of triacylglycerols (TAGs) into free fatty acids (FFAs) and glycerol in adipocytes.
  • Activation Mechanism:
    • Key hormones involved include glucagon, epinephrine, norepinephrine, and cortisol.
    • Under fasting or stress, these hormones activate adenylyl cyclase, converting ATP to cAMP.
    • cAMP levels increase, which activates protein kinase A (PKA).
    • PKA phosphorylates and activates lipolytic enzymes: TAG lipase, hormone-sensitive lipase (HSL), and monoglyceride lipase (MGL).
Inhibition of Lipolysis
  • Insulin, nicotinic acid, and prostaglandins inhibit lipolysis.
    • They act by inhibiting adenylyl cyclase, which lowers cAMP levels.
    • Lower cAMP results in less active PKA, which leads to the inactivation of lipolytic enzymes.
  • Caffeine, thyroid hormones, and theophylline inhibit phosphodiesterase, preventing the breakdown of cAMP. This results in elevated cAMP levels, activating PKA and thereby enhancing lipolysis.

BETA OXIDATION OF FATTY ACIDS

  1. Regulation by availability of fatty acids:

    • Adipose tissue releases FFAs into the bloodstream via lipolysis.
    • FFAs are taken up by tissues (e.g., muscle, liver) and converted to fatty acyl-CoA.
    • Conversion Process: Fatty acyl-CoA is converted to fatty acylcarnitine by Carnitine palmitoyl transferase I (CPT I), which is then transported into the mitochondria.
    • Inside mitochondria, it's converted back to fatty acyl-CoA by Carnitine palmitoyl transferase II (CPT II), allowing fatty acyl-CoA to enter β-oxidation for energy production.
    • If fatty acid supply is low, β-oxidation slows down.

  2. Regulation by Transport into Mitochondria:

    • Malonyl-CoA is a critical regulator in this process.
    • High glucose levels lead to increased malonyl-CoA production, which inhibits CPT I, blocking fatty acid to mitochondrial import.
    • Result: High glucose decreases β-oxidation.
    • Dual Control System:
      • Hormonal control via lipolysis (insulin, glucagon, epinephrine).
      • Metabolic feedback via malonyl-CoA, linking carb metabolism to fat metabolism.
      • Ensures β-oxidation is inhibited during fed state and activated during fasting/exercise.

KETOGENESIS

  1. Trigger: Increased adipose tissue lipolysis due to low insulin/high glucagon catecholamines leads to increased free fatty acids (FFAs) in blood.

  2. Regulation: Low levels of malonyl-CoA activate CPT I, allowing FFAs to enter liver for conversion to fatty acyl-CoA, leading to β-oxidation.

    • In starvation or diabetes, decreased insulin reduces activity of acetyl-CoA carboxylase (ACC), lowering malonyl-CoA levels and activating CPT I thus promoting β-oxidation.
    • Excess acetyl-CoA enters the TCA cycle. In starvation, prolonged fasting can saturate the TCA cycle, diverting excess acetyl-CoA into ketogenesis.

  3. Induction of HMG-CoA Synthase:

    • HMG-CoA synthase is the rate-limiting enzyme for ketogenesis, upregulated by low insulin/high glucagon (transcriptional) and high fatty acid supply (substrate-driven).

  4. Role of ATP availability:

    • Low ATP activates AMPK, which inhibits ACC, lowering malonyl-CoA, activating CPT I, hence enhancing β-oxidation.
    • In starvation/diabetes, increased ATP demand promotes fat oxidation for energy.

FATTY ACID SYNTHESIS

  • Regulation of Acetyl-CoA Carboxylase (ACC):
    • Allosteric activator: Citrate increases malonyl-CoA levels, promoting fatty acid synthesis.
    • Allosteric inhibitors: Palmitic acid signals sufficient fatty acid synthesis, inhibiting ACC.
Hormonal Regulation
  • Glucagon and Epinephrine activate PKA, which phosphorylates ACC, inactivating it during fasting/stress.
  • Conversely, Insulin promotes fatty acid synthesis by activating phosphatases to dephosphorylate ACC, activating it.
Regulation by AMPK
  • Low energy levels (high AMP) activate AMPK, which inhibits ACC and fatty acid synthesis.
Transcriptional Regulation
  • High Carbohydrate Diet:
    • Insulin activates SREBP-1c and ChREBP, enhancing ACC gene expression and promoting fatty acid synthesis.
  • Low Carbohydrate Diet:
    • Low insulin/high glucagon represses SREBP/ChREBP activity, reducing ACC gene expression.
Connection to Metabolism
  • High ACC leads to high malonyl-CoA, promoting synthesis and inhibiting oxidation. Low ACC has the opposite effect.
  • Active ACC → malonyl-CoA high → synthesis on, oxidation off.
  • Inactive ACC → malonyl-CoA low → synthesis off, oxidation on.

CHOLESTEROL BIOSYNTHESIS

  1. Feedback Repression: Cholesterol inhibits its own synthesis by repressing HMG-CoA reductase transcription when cellular cholesterol is high.

  2. Covalent Modification:

    • Phosphorylation by AMPK inactivates HMG-CoA reductase under low energy conditions.
    • Dephosphorylation reactivates HMG-CoA reductase, allowing synthesis when energy levels improve.

  3. Hormonal Regulation:

    • Insulin stimulates phosphatase to activate HMG-CoA reductase, enhancing cholesterol synthesis.
    • Glucagon, epinephrine, norepinephrine promote phosphorylation/inactivation via PKA.

  4. SREBP-SCAP System:

    • SREBP synthesized as an inactive precursor in ER, bound to SCAP.
    • Low cholesterol promotes transport of SREBP from ER to Golgi, leading to cleavage and activation.
    • Active SREBP induces transcription of genes for cholesterol synthesis.
    • High cholesterol binds SCAP, blocking SREBP transport and preventing gene transcription.

DISORDERS OF LIPID METABOLISM

FATTY LIVER / HEPATIC STEATOSIS
  • Definition: Excessive accumulation of triglycerides in hepatocytes due to imbalance between fat synthesis/import and export.
  • Causes:
    1. Increased synthesis and delivery of hepatic fat: In insulin resistance, lipolytic enzymes are uncontrolled, flooding the liver with FFAs that get reesterified into triglycerides.
    2. Impaired export of triglycerides: VLDL packaging and secretion is hindered by toxic injury, nutritional deficiencies, or any VLDL synthesis disruption.
    3. Chronic Alcohol Consumption: Alters NADH/NAD+ ratio inhibiting fatty acid oxidation and promoting lipogenesis while depleting lipotropic factors necessary for VLDL assembly.
KETOSIS
  • Definition: A metabolic state transitioning from glucose usage to fat-derived ketone bodies for energy, marked by elevated blood levels of ketones.
  • Occurs during fasting, prolonged exercise, or low-carb diets, ensuring energy supply to vital organs.
  • Involves hormonal changes (low insulin, high glucagon), boosting fat breakdown into FFAs, which are converted into ketone bodies in the liver.
  • Pathological ketosis (DKA) erupts from insulin deficiency in diabetes, leading to life-threatening conditions.
HYPERCHOLESTEROLEMIA
  • Definition: Elevated cholesterol levels, particularly LDL, increasing risks for cardiovascular diseases.
  • Causes: Genetic (familial hypercholesterolemia) or secondary lifestyle factors.
    • Hypothyroidism reduces LDL receptor expression, impairing blood cholesterol clearance.
    • Nephrotic syndrome triggers overproduction of lipoproteins due to massive proteinuria.
    • Diabetes results in insulin resistance leading to excessive VLDL production.
ATHEROSCLEROSIS
  • Definition: A cardiovascular disease characterized by plaque formation within blood vessels, marking it as an inflammatory condition.
  • Initial plaque development involves LDL cholesterol accumulation and oxidation, leading to inflammation, foam cell formation, and eventual fatty streak and plaque development, culminating in potential myocardial infarction (heart attack) due to ruptured plaques blocking blood flow.
Process of Atherosclerosis Development

(a) Normal Arterial Wall:

  • Composed of endothelial cells, elastic connective tissue, and smooth muscle cells.

(b) Fatty Streak:

  • LDL cholesterol accumulation leads to oxidation, macrophage involvement, and foam cell creation.

(c) Stable Fibrous Plaque:

  • Characterized by fibrous tissue formation and vascular remodeling in response to inflammation.

(d) Vulnerable Plaque:

  • Macrophages can destabilize plaques leading to rupture and consequent clot formation, impacting blood flow significantly.
  • Such events can precipitate heart attacks when occurring in coronary arteries.