Summary Notes

I. Describe how excess carbohydrate and/or amino acid consumption leads to fatty acid and triacylglycerol production

Excess carbohydrates are metabolized into acetyl-CoA through glycolysis and pyruvate dehydrogenase activity. When glycogen stores are full and energy demand is low, this acetyl-CoA is diverted to fatty acid synthesis (lipogenesis). Similarly, amino acids can be deaminated and converted into acetyl-CoA or TCA intermediates that feed into lipogenesis. The synthesized fatty acids are esterified to glycerol-3-phosphate (from glycolysis) to form triacylglycerols (TAGs), which are either stored in adipose tissue or packaged into VLDLs in the liver.

II–III. Precursor of fatty acid biosynthesis

Acetyl-CoA is the immediate precursor of fatty acid synthesis.

  • A. Generation: Acetyl-CoA is generated in the mitochondrial matrix via:

    • Pyruvate dehydrogenase (glucose → pyruvate → acetyl-CoA)

    • Catabolism of ketogenic amino acids

  • B. Transport: Acetyl-CoA cannot cross the mitochondrial membrane directly. It combines with oxaloacetate to form citrate, which is transported to the cytoplasm. ATP-citrate lyase cleaves citrate to regenerate acetyl-CoA and oxaloacetate.

  • C. Other precursors generated:

    • Oxaloacetate is converted to malate, then to pyruvate by malic enzyme, which produces NADPH—a necessary reducing agent for lipogenesis.

IV. Fatty Acid Biosynthesis Complex

  • A. Description: Fatty acid synthase (FAS) is a multi-enzyme complex located in the cytoplasm. It synthesizes palmitate by sequentially adding 2-carbon units from malonyl-CoA to a growing acyl chain.

  • B. Six recurring reactions (each cycle after loading step):

    1. Condensation (acetyl + malonyl → β-ketoacyl)

    2. Reduction (β-keto → β-hydroxyacyl via NADPH)

    3. Dehydration (β-hydroxyacyl → trans-enoyl)

    4. Second reduction (enoyl → saturated acyl via NADPH)

    5. Translocation (shift to growing chain site)

    6. Repeat cycle (until 16-carbon palmitate is formed)

  • C. Coenzymes required: NADPH (from PPP and malic enzyme), biotin (in ACC reaction)

  • D. Final product: Palmitate (C16:0)

V. Other reactions necessary for complete fatty acid biosynthesis

  • Elongation: Palmitate can be elongated in the ER to stearate or longer fatty acids.

  • Desaturation: Desaturases introduce double bonds to form unsaturated fatty acids.

VI. Compare/Contrast: β-oxidation vs Fatty Acid Biosynthesis

  • Location:

    • β-oxidation: Mitochondria

    • Lipogenesis: Cytoplasm

  • Coenzymes:

    • β-oxidation: NAD⁺, FAD

    • Lipogenesis: NADPH

  • Pathway direction:

    • β-oxidation: Degradative

    • Lipogenesis: Synthetic

VII. Control points of fatty acid biosynthesis

  • A. Allosteric control:

    • Acetyl-CoA carboxylase (ACC) is activated by citrate and inhibited by palmitoyl-CoA.

  • B. Reversible covalent modification:

    • ACC is inactivated by phosphorylation (via AMP-activated protein kinase) and activated by dephosphorylation (via insulin signaling).

  • C. Hormonal control:

    • Insulin stimulates ACC and FAS expression, promoting lipogenesis.

    • Glucagon and epinephrine inhibit lipogenesis via phosphorylation.

    1. Integration with β-oxidation:

      • Malonyl-CoA (product of ACC) inhibits CPT1, preventing fatty acid entry into mitochondria for β-oxidation during active lipogenesis.

    2. Triacylglycerol cycle & glyceroneogenesis:

      • TAGs are continually hydrolyzed and re-esterified in adipose tissue.

      • Glyceroneogenesis (especially in fasting) generates glycerol-3-phosphate for TAG re-synthesis from non-glucose sources (e.g., pyruvate).

VIII. Integration with carbohydrate metabolism

  • A. Regulation in tissues:

    • Liver: Converts glucose → acetyl-CoA → fatty acids

    • Adipose tissue: Stores fatty acids as TAGs; limited acetyl-CoA production

    • Skeletal muscle: Primarily oxidizes fatty acids; not involved in synthesis

  • B. Hormonal regulation:

    • Insulin promotes glycolysis, lipogenesis, and TAG storage

    • Glucagon stimulates lipolysis and inhibits lipogenesis

IX. Synthesis of other lipid types

  • A. Phosphatidate: Formed by acylation of glycerol-3-phosphate with fatty acyl-CoAs

  • B. Triacylglycerols: Formed by esterification of phosphatidate (via phosphatidate phosphatase → DAG → TAG)

  • C. Phosphoglycerides: Formed from DAG by attaching head groups (e.g., choline, ethanolamine)

  • D. Ether lipids: Synthesized in peroxisomes and ER; involves ether bond formation at sn-1 position

  • E. Sphingosine/Ceramide: Synthesized from serine and palmitoyl-CoA; ceramide is a central intermediate

X. Triacylglycerol Cycle and Glyceroneogenesis

The TAG cycle involves continuous breakdown and re-formation of TAGs in adipose and liver tissue. Glyceroneogenesis allows TAG re-synthesis in fasting states, using precursors like pyruvate (not glucose), especially important in adipose tissue.

XI. Cholesterol Biosynthesis

  • A. General synthesis:

    • Acetyl-CoA → HMG-CoA → mevalonate → isoprenoids → squalene → cholesterol

  • B. Precursor:

    • Acetyl-CoA, generated in mitochondria and transported as citrate

  • C. Similarity to ketone body synthesis:

    • Both begin with acetyl-CoA → HMG-CoA

  • D. Differences from ketone body synthesis:

    • Cholesterol synthesis continues with HMG-CoA reductase, while ketogenesis uses HMG-CoA lyase

  • E. Other isoprenoids:

    • Coenzyme Q (ubiquinone), dolichol, prenylated proteins

  • F. Control point(s):

    • HMG-CoA reductase is the rate-limiting enzyme

  • G. Regulation:

    • Controlled by transcription (SREBP), phosphorylation, degradation, and feedback inhibition by cholesterol

XII. What If Question: Why does someone with excess calorie intake but low cholesterol intake still have high cholesterol?

Because endogenous cholesterol synthesis increases with excess acetyl-CoA availability from carbohydrates and amino acids. Dietary cholesterol isn't the sole source—HMG-CoA reductase activity ensures internal synthesis to meet cellular demand.