Lecture Notes on Lipid Synthesis - 29

Lipid Synthesis Overview

  • Key Topics:

    • Storage and membrane lipids

    • Cholesterol synthesis

    • Cholesterol regulation and transport

Lipid Pathways

  • Key Components:

    • Glucose

    • DHAP (Dihydroxyacetone phosphate)

    • Glycerol 3-phosphate

    • Phosphatidate

  • Tissue Involvement:

    • Liver

    • Adipose tissue

  • Active Pathways:

    1. Glycolysis

    2. Triacylglycerol breakdown

    3. Triacylglycerol synthesis

    4. Phospholipid synthesis

Phosphatidate

  • Importance:

    • Acts as a backbone in lipid synthesis.

    • Formed by the addition of 2 fatty acids to glycerol 3-phosphate.

Triacylglycerol Formation

  • Formation Steps:

    • Phosphatidate links to a third fatty acid to form triacylglycerol, facilitated by the triacylglycerol synthetase complex located on the ER membrane.

  • Storage and Usage:

    • Stored in adipose tissue (85% of energy storage) or transported to muscles as fuel.

Phospholipids

  • Components:

    • Backbone (glycerol or sphingosine)

    • Two fatty acids

    • Phosphorylated alcohols

  • Functions:

    • Fundamental to cell membranes and involved in lung surfactants and signaling molecules.

Glycerophospholipids

  • Formation:

    • Comprised of DAG and an alcohol, requiring conversion into activated precursors.

    • Activation: Reaction with CTP to form CDP-diacylglycerol, which can react with -OH in an alcohol to form phospholipids.

  • Products:

    • Different alcohols produce various phospholipids, such as phosphatidylinositol and cardiolipin.

Regulation of Lipid Synthesis

  • Regulatory Mechanisms:

    • Relative abundances of diacylglycerol and phosphatidate determine lipid levels.

    • Increased activity of phosphatidic acid phosphatase leads to diacylglycerol.

    • Diacylglycerol kinase activity increases phosphatidate.

  • Impact of Regulation:

    • Loss of phosphatase activity correlates with body fat loss and insulin resistance.

Sphingolipids

  • Characteristics:

    • Found in eukaryotic cells with a sphingosine backbone.

    • Ceramide is the first sphingolipid formed by the addition of fatty acids to sphingosine.

  • Head Groups:

    • Variability among sphingolipids, including sphingomyelin (myelin sheath), cerebrosides, and gangliosides (immune responses).

  • Functions:

    • Important for cell recognition, comprising ABO blood group determinants and pathogenic-binding sites.

Cholesterol

  • Vital Functions:

    • Maintains cell membrane fluidity and serves as a precursor for steroid hormones (e.g., testosterone, estradiol).

  • Synthesis Steps:

    1. Formation of HMG-CoA from acetyl CoA.

    2. Regulated step by HMG-CoA reductase.

    3. Assembly of squalene from five-carbon precursors.

    4. Cyclization of squalene to produce cholesterol.

Regulation of Cholesterol Synthesis

  • Mechanisms:

    • Feedback inhibition based on cholesterol levels impacts HMG-CoA reductase activity.

    • Various regulatory pathways include transcriptional, translational controls, and protein stability adjustments.

Cholesterol Transport

  • Transport Mechanism:

    • Cholesterol packed into lipoproteins for transport, with sorting by density (e.g., VLDLs, IDLs, LDLs, and HDLs).

    • LDLs deliver cholesterol to tissues, while HDLs facilitate reverse transport back to the liver.

  • Clinical Insight:

    • Familial hypercholesteremia leads to excess cholesterol and LDL in plasma, resulting in health risks like atherosclerosis.