Lipid metabolism Flashcards
What are the functions of fatty acids?
1) Serves as a major energy reserve (they are esterified in the form of TAGs to be stored in adipose tissue)
- Most cells can oxidize fatty acids to produce energy
2) A source of ketone bodies (in the liver)
3) A structural component of the membrane lipids and proteins
4) Precursor for hormones like prostaglandins
- Alteration in the metabolism of FFA is associated with obesity and diabetes
What are the two essential features of the fatty acid structure?
- Carboxylic acid moiety + Long hydrocarbon chain = Fatty acid
1) Long hydrocarbon chain (linea, usually contains an even number of carbons 4-30)
2) There is a carboxylic acid group in carbon 1 (gives the Fatty acid ists amphipathic nature
- Fatty acids are transported wither with a lipoprotein or in the circulation associating with albumin
What are the different forms of fatty acids in our body?
1) Free
2) TAGs
3) Cholesterol esters
What are the sources of fatty acids?
1) The diet supplies us with the essential fatty acids (like linoleic)
2) Conversion of excess carbohydrates and proteins from the diet into FA and then to TAGs for storage
- Excess proteins are converted to Ketogenic amino acids then fatty acids then TAGs
- Carbohydrates are converted to glycolysis then acetyl CoA, in excess of ATP acetyl CoA is converted to fatty acids
What is the function of lipoprotein lipase?
It clears the triglycerides in the chylomicron (lipoprotein)
- Free fatty acids can then be cleared as fat in adipose tissue or as TAGs or used to generate energy
What happens to the fatty acids in the liver?
It is re-esterified into TAGs which will be taken later to the peripheral tissue by VLDL
What are the functions of insulin?
1) Stimulates lipoprotein lipase in the capillaries
2) It stimulates the synthesis of fatty acids and TAG in the liver and adipose tissue
3) It inhibits the hormone-sensitive lipase in the adipose tissue
What are the stages of fatty acid synthesis?
1) Transport of acetyl CoA into the cytosol
2) Carboxylation of the acetyl CoA
3) Assembly of the FA chain
Where does the synthesis of FA occur?
It mainly occurs in the cytoplasm in the liver, adipocytes, and in the mammary gland during lactation
- When glucose is plentiful, large amounts of acetyl CoA are produced by glycolysis which can be used for fatty acid synthesis
How is the Acetyl CoA transported to the cytosol?
Acetyl CoA cannot cross the enzyme membrane and thus it is converted to citrate by combining it with oxaloacetate via a condensation reaction to cross the membrane of the enzyme
- The availability of ATP and citrate stimulates the synthesis of fatty acids
Describe the carboxylation of the acetyl CoA to form Fatty acid
- Acetyl CoA carboxylase (ACC) catalyzes a 2-step reaction where the acetyl-CoA is carboxylated to form malonyl-CoA (using CO2, ATP, & Biotin as a cofactor)
What regulates the enzyme?
1) Phosphorylation (the active form is the dephosphorylated one)
2) Activated High citrate and insulin
3) Inhibited by glucagon and epinephrine
What is the committed step in the synthesis of fatty acids?
- The conversion of acetyl-CoA to malonyl-CoA via Acetyl-CoA carboxylase
What is the enzyme fatty acid synthase?
- Formed of two polypeptides performing a seven-step reaction, it is a multifunctional, dimeric enzyme that is transcriptionally regulated
- This enzyme is responsible for the elongation of the fatty acid chain producing palmitic acid at the end, requiring NADPH
How is fatty acid synthase regulated?
- In the liver:
1) The expression of fatty acid synthase is stimulated by insulin (storing the excess glucose as fat)
2) Fatty acid synthase transcription is diminished by the polyunsaturated fatty acids, via its suppression of the production of the response element binding protein (SREBP)
- In the fat cells
1) Leptin inhibits the expression of SREBP-1 and fatty acid synthase
- Leptin is produced by fat cells in response to excess fat storage (decreasing food intake), leptin resistance is associated with obesity
How does the polyunsaturated fatty acid diminish the transcription of fatty acid synthase?
By suppressing the production of sterol response element binding protein (also done by leptin)
Where does the synthesis of triglyceride occur?
- TGs is formed from glycerol and fatty acids
- Liver (packed and released in VLDL)
- Adipose tissue (storage)
- An imbalance between the synthesis and release will cause fatty liver disease (accumulation of TAG in tissues other than adipose usually indicates a pathological state like NAFLD)
What happens to the TGs in the fasting state?
TAGs undergo lipolysis in response to hypoglycemia and stress via the hormone-sensitive lipase (HSL)
What are the steps of the b-oxidation of fatty acids?
- Requires the transportation of fatty acid into the mitochondrial matrix via a carrier called carnitine shuttle
1) Oxidation
2) Hydration
3) Oxidation
4) Cleavage
- FA oxidation occurs in the peroxisomes of the mitochondria, yielding CO2, H2O, NADH, FADH2 & 129 ATP
What will happen if there is carnitine deficiency?
- A carnitine shuttle is required for the transportation of fatty acid into the mitochondrial matrix
- Deficiency in carnitine will lead to a reduction in the ability to use long-chain fatty acids
- A deficiency in carnitine could be due to primary or secondary cause of liver disease, or a secondary cause of anti-seizure drugs
- Deficiency of carnitine can lead to severe hypoglycemia (as glucose is being used more for energy since fatty acid long chain cannot be metabolized) and severe cases might lead to death
How does the fatty acid enter into the mitochondria?
1) Fatty acyl synthase activates the fatty acid (in the outer mitochondrial membrane)
2) Carnitine acyltransferase-1 will transfer the fatty acyl group to carnitine (in the outer mitochondrial membrane)
3) Fatty acyl-carnitine is shuttled across the inner mitochondria via the transporter in the inner membrane
4) Carnitine acyltransferase-2 will then transfer the fatty acyl group back to the CoA at the mitochondrial matrix
- Short and medium-chain fatty acids can diffuse freely into the mitochondria
How are the fatty acids activated in the b-oxidation?
- The only step that requires ATP, which is accomplished in two steps:
1) b-oxidation for the odd number of carbon atoms yielding acetyl-CoA and propionyl-CoA
2) Propionyl-CoA is then converted to the Krebs cycle intermediate succinyl-CoA involving vitamin B12
What are the main organs that synthesizes cholesterol?
1) Liver
2) Intestine
3) Adrenal cortex
4) Reproductive organs
- Controlled by insulin and glucagon, the first HMG-CoA synthase synthesizes the first molecule, then it undergoes reduction via HMG-CoA reductase forming mevalonate (the rate-limiting step)
What are the functions of the cholesterol?
1) Steroid hormones
2) Plasma membrane
3) Bile acids
4) Vitamin D synthesis
