Updated: 7/9/2019

Fatty Acid Metabolism

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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
          • 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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