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Updated: Nov 23 2021

Fatty Acid Metabolism

  • Overview
    • Structure
      • long chain of carbons with carboxyl group on one end
      • can have a variable amount of double bonds
        • double bonds make a fat unsaturated
        • naturally in a cis configuration
          • trans fats are unnatural and created via hydrogenation of vegetable oils
            • ↑ risk of atherosclerosis
        • double bonds ↓ melting temperature
          • plant fat (e.g. olive oil) is unsaturated and liquid at room temperature
          • animal fat (eg. butter) is saturated and solid at room temperature
      • nomenclature
        • e.g. palmitic acid
          • C16:0
            • 16 carbons with no double bonds
              • numbered with carboxyl carbon as 1
        • e.g. linoleic acid
          • C18:2 (9,12)
            • 18 carbons with 2 double bonds (one at the 9th and one at the 12th carbon)
        • omega system
          • count opposite to the numbered system (i.e. carboxyl carbon is counted last)
          • used to number unsaturated fats
          • e.g. linoleic acid
            • omega 6 family
            • double bond at position "12" is 6 in from the opposite side (18 carbons in total)
    • Essential fatty acids (FA)
      • cannot be synthesized
      • examples
        • linoleicacid
          • omega 6
          • can be used as a precursor for arachidonic acid
            • becomes an essential fatty acid if linoleic acid is absent
        • linolenic acid
          • omega 3
            • ↓ risk of CV disease
              • remember: omega 3 saves you from triple bypass
            • found in cold water fish, nuts
    • Transport
      • see Lipoprotein topic
  • Synthesis
    • FA synthesis
      • pyruvate (carbohydrate) → acetyl-CoA
        • activated by insulin
        • functions to store excess carbs as fat
        • occurs in the mitochondria via pyruvate dehydrogenase
      • acetyl-CoA + oxaloacetate → citrate
        • shuttled out of mitochondria into cytoplasm
          • citrate shuttle
        • split back to acetyl-CoA and oxaloacetate
      • acetyl-CoA + CO2→ malonyl-CoA
        • catalyzed by acetyl-CoA carboxylase
        • biotin required
        • activated by insulin
      • malonyl-CoA → CO2 + 2 carbons on fatty chain
        • catalyzed by FA synthase
        • requires NADPH
        • humans make palmitic acid (16:0) as stored fat
          • only de novo fat possible
        • for 1 palmitic acid requires
          • 8 acetyl-CoA
          • 7 ATP
          • 14 NADPH
  • Catabolism
    • Break down via β-oxidation
      • occurs in hepatocytes, myocytes, adipocytes
        • neurons cannot use fat as energy
          • FAs do not cross BBB
      • pathway location differs based on length of FAs
        • short/medium (2-12 carbons)
          • diffuse in mitochondria
        • long (14-20 carbons)
          • utilizes carnitine shuttle
            • carnitine added to FA in the intermembrane space of the mitochondria
              • catalyzed by carnitine acyltransferase (CAT) -1
                • inhibited by malonyl-CoA so as to prevent newly synthesized FAs from being degraded
            • carnitine: FA transported into the matrix
              • catalyzed by the carnitine transporter
              • primary carnitine deficiency
                • caused by carnitine transporter defect
                  • presentation
                    • lethargy
                    • irritability
                    • nonketotic / hypoketotic hypoglycemia
                    • triggered by catabolic states (e.g., fasting or illness)
            • carnitine exchanged for CoA
              • catalyzed by carnitine acyltransferase (CAT)-2
              • clinical importance
                • myopathic CAT deficiency
                  • presentation
                    • myoglobinuria
                    • muscle aches/weakness
                    • ↑ TG content in muscles
                      • unable to use as energy
                    • provoked by prolonged use of muscle
        • very long (>20 carbons)
          • oxidized in peroxisome
    • β-oxidation pathway
      • occurs in the mitochondrial matrix
      • reverses FA synthesis
        • removing an acetyl-CoA and producing NADH and FADH2
          • catalyzed by fatty acyl-CoA dehydrogenase
            • two types
              • long-chain acyl-CoA dehydrogenase (LCAD)
              • medium-chain acyl-CoA dehydrogenase (MCAD)
            • blocked by ackee fruit toxin
        • creates most of the energy used by the liver
          • acetyl-CoA created in liver does not enter the citric acid cycle
            • forms ketones
              • see Ketone bodies topic
      • clinical importance
        • MCAD deficiency
          • presentation
            • non-ketotic hypoglycemia
            • C8-C10 acyl carnitines in the blood
              • liver unable to break FAs down further than C8-C10
            • no ketone bodies
              • liver unable to produce ketones from β-oxidation
            • fasting hypoglycemia
              • liver unable to produce enough energy from β-oxidation to supply gluconeogenesis
            • symptoms often precipitated by infection or stress
          • treatment
            • low fat diet with frequent meals of high carbs
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