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Chapter 8: Lipid Metabolism

1. PURPOSE

  1. Lipids make up the final big category of metabolism, in addition to carbohydrates and amino acids

  2. Lipids are not only an efficient source of energy but also important for cell structure and signaling hormones

  3. This chapter prioritizes topics like cholesterol and lipid transport, which are especially relevant to cardiovascular disease

2. LIPID SYNTHESIS

  1. Recall acetyl-CoA from Chapter 5: Link between glycolysis and TCA cycle

  2. Acetyl-CoA is also the branch point toward lipid synthesis

  3. Overall, lipid synthesis can branch in 2 ways

    1. Fatty acid synthesis: Fatty acids (FAs), triglycerides (TGs) for fat storage

    2. Cholesterol synthesis: Important for cell membrane structure, steroid synthesis, and bile acid synthesis

  4. Each of these relates to common topics in other systems, such as atherosclerosis, hypercholesterolemia, and diabetes mellitus

3. FATTY ACID METABOLISM

  1. Much lower yield than most of the other side pathways we'll talk about

  2. Acetyl-CoA is the link between glycolysis and fatty acids

  3. Key synthesis steps

    1. Branch point is at citrate—citrate is leaving mitochondria via citrate shuttle for cytoplasm where it:

      • Regulates glycolysis by inhibiting PFK-1 (prevent excess glycolysis)

      • Converts back into acetyl-CoA for fatty acid synthesis

    2. Biotin (B7) is required for synthesis

    3. Synthesis occurs mainly where you would expect: Liver, and high-fat tissues that store lots of energy (adipose, mammary glands)

  4. Key breakdown steps

    1. Shuttle into the mitochondria to incorporate back into TCA cycle via carnitine shuttle

    2. Breakdown via β-oxidation to acetyl-CoA to enter directly into TCA cycle

    3. Even-numbered fatty acids cannot produce glucose (e.g., local energy source)

    4. Lipid metabolism in the liver is a major source of ketone bodies (see Chapter 9)

  5. Clinical: Fatty acids (like glycogen) are a major energy source especially for muscle cells

    1. Systemic primary carnitine deficiency—can't get long chain fatty acids into the mitochondria leading to accumulation

      • Weakness, hypotonia—lack of energy, especially during fasting

      • Hepatomegaly—liver function is impaired

      • Hypoketotic hypoglycemia—liver can't process fatty acids for ketogenesis during fasting; and tissues that could have used fatty acids or ketone bodies for energy end up using up too much glucose

    2. Medium-chain acyl-CoA dehydrogenase deficiency—later in the pathway; can't break down 8 to 10 carbon FAs into acetyl-CoA

      • Similar symptoms (hypoketotic hypoglycemia) but roughly speaking, more severe (infancy/early childhood)

      • Additionally: Vomiting, neurologic symptoms (brain uses ketones under certain conditions), and liver dysfunction

      • Treatment: Avoid lipolysis by regular food intake

Figure 8-1.

Overview of acetyl-CoA usage pathways.

A set of reactions show the conversion of pyruvate to different fatty acids, ketones, and cholesterol. In the first step, pyruvate forms acetyl coenzyme A, which undergoes three reactions. The first is the T C A cycle. The second is the formation of malonyl coenzyme A, and the third is the formation of H M G coenzyme A. The malonyl coenzyme A in turn forms fatty acids, while H M G coenzyme A forms ketones in the mitochondria and cholesterol in the cytosol. The caption reads, “overview of acetyl coenzyme A usage pathways.”
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Figure 8-2.

Fatty acid synthesis and breakdown.

A set of reactions in the cytosol and mitochondria shows the synthesis and degradation of fatty acids. The initial steps occur in the cytosol, where the citrate first forms acetyl coenzyme A, which in turn forms malonyl l coenzyme A. The malonyl l coenzyme A then forms fatty acyl coenzyme A, which in turn forms fatty acids. All the steps until the formation of fatty acids is labeled synthesis. The remaining steps are labeled degradation. In degradation, fatty acids are converted to fatty acyl l coenzyme A in the presence of fatty acyl l coenzyme A synthase, which undergoes carnitine shuttle that transfers the fatty acyl l coenzyme A into the mitochondria. The remaining reactions occur inside the mitochondria, where the fatty acyl l coenzyme A converts to acetyl l coenzyme A, which undergoes the T C A cycle to release citrate within the mitochondria This citrate undergoes citrate shuttle to be transferred outside to the cytosol where the first step is repeated. The caption reads, “fatty acid synthesis and breakdown.”
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4. CHOLESTEROL SYNTHESIS

  1. Synthesis takes place in the cytosol of virtually all tissues, though liver is a major source

  2. Carefully balanced with uptake through LDL receptors

  3. The cholesterol synthesis pathway can be distilled down to 3 steps for the ...

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