LIPID METABOLISM : LIPID METABOLISM Dr. V. Siva Prabodh MD
Dept. of Biochemistry
NRI Medical College Dietary Fatty Acids : 2 Dietary Fatty Acids Comprise 30-60% of caloric intake in average American diet
Triacylglycerols, phospholipids, sterol esters
Principal sources: dairy products, meats Digestion of Dietary Triacylglycerols : 3 Digestion of Dietary Triacylglycerols Occurs in duodenum
Bile salts (emulsification)
Alkaline medium (pancreatic juice) Pancreatic
lipases OH OH TAG MAG Intestinal
Fatty Acids Blocked by Orlistat (“Fat Blocker”) Slide 4: 4 Epithelial Cell (Intestinal Wall) Intestinal lumen MAG Glycerol Fatty Acids TAG Lipoprotein Chylomicrons Lymphatics Blood (bound to albumin) Adipose Tissue
And Muscle Slide 5: 5 Adipocytes Lipid Metabolism : Lipid Metabolism Lipid Metabolism : Lipid Metabolism Slide 9: 9 Adipose Cell Hormone
(Adrenalin, Glucagon, ACTH) Receptor (7TM) ATP c-AMP Adenylyl
Cyclase Activates Activates lipase Triacylglycerols Glycerol +
Fatty acids Blood Lipolysis Insulin
step Lipid Metabolism : Lipid Metabolism Beta Oxidation of Fatty acids : Beta Oxidation of Fatty acids Beta Oxidation is the process where energy is produced from Lipids.
Beta oxidation is the oxidation over the β -Carbon of hydrocarbon chain of fatty acids by a sequential cleavage of two carbon atoms. Slide 12: The break down of a fatty acid to acetyl-CoA Occurs in the mitochondria STRICTLY AEROBIC Acetyl-CoA is fed directly into the Krebs cycle Overproduction causes KETOSIS Slide 13: → β -oxidation takes place in Mitochondria
→ Fatty acids which are participating in β-oxidation undergo activation to form Fatty acyl CoA
→ Activation of fatty acid takes place in cytoplasm, requires 2 high energy bonds and enzyme is Thiokinase or fatty acyl Co A synthetase.
→ The activated fatty acids which are present in cytoplasm enters into mitochondria with the help of Carnitine.
CARNITINE is β – hydroxy trimethyl amonium butrate
It is synthesized from Lysine and Methionine in Liver & Kidney. Lipid Metabolism : Lipid Metabolism Slide 15: Transport into Mitochondria depends on Carnitine FA~CoA FA~Carnitine FA~Carnitine Carnitine Translocase β – oxidation proper : β – oxidation proper There are 4 steps in β – oxidation
Step I – Oxidation by FAD linked dehydrogenase
Step II – Hydration by Hydratase
Step III – Oxidation by NAD linked dehydrogenase
Step IV – Thiolytic clevage Thiolase Beta Oxidation : Beta Oxidation Beta Oxidation : Beta Oxidation Beta Oxidation : Beta Oxidation Beta Oxidation : Beta Oxidation Beta Oxidation : Beta Oxidation Palmitic (16 c) Beta Oxidation : Beta Oxidation Palmatic acid(16 c) 7 8 Energetics: : Energetics: Palmitic acid (16 C) needs 7 cycles of beta-oxidation, which gives rise to
8 molecules of Acetyl Co A
8 acetyl Co A x 12 = 96 ATP
7 FADH2 x 2 = 14 ATP
7 NADH x 3 = 21 ATP
Total 131 ATP
In initial activation Palmic acid → Palmitoyl Co A requires 2 high energy phosphates, so net is 131 – 2 = 129 ATP Slide 24: 24 American Golden Plover Slide 25: 25 Arctic Tern Slide 26: 26 Camel Acetyl CoA : Acetyl CoA Regulation: : Regulation: Availability of FFA regulates β-oxidation. The availability of FFA is controlled by
Glucagon : Insulin ratio
Glucagon Increases FFA level
Insulin decreases FFA level
(2) CAT – I regulates entry of Fatty acyl Co A into mitochondria.
Malonyl Co A Inhibits CAT – I activity. Disorders of β-Oxidation : Disorders of β-Oxidation SIDS : Sudden Infant death syndrome.
Unexpected death in healthy Infants, usually overnight.
Deficiency: Medium chain acyl Co A dehydrogenase. The sudden death is due to blockade of β-Oxidation due to absence of MCAD.
■ Jamaican vomiting sickness:
Symptoms: Severe hypoglycemia
Vomitings Convulsion, coma & death
Causes : Hypoglycin A which is present in Unripe ackee fruit.
Hypoglycin A inhibits Acyl CoA dehydrogenase and thus β-Oxidation is blocked. Beta Oxidation of Odd chain Carbon Fatty Acids : 32 Beta Oxidation of Odd chain Carbon Fatty Acids 5 Cycles 5 CH3COSCoA + CH3CH2COSCoA Propionyl CoA D-Methylmalonyl
CoA Succinyl CoA TCA Cycle Propionyl CoA
ATP/CO2 Epimerase Mutase
Vit. B12 β-Oxidation of odd chain fatty acids : β-Oxidation of odd chain fatty acids In odd chain fatty acids in the last and final β-Oxidation cycle, a three carbon fragment is left behind (Propionyl CoA)
Fate of Propionyl CoA:
α – Methylmalonyl CoA
Succinyl CoA Disorder related to β-Oxidation in odd chain fatty acids. : Disorder related to β-Oxidation in odd chain fatty acids. ═ Methylmalonic acidemia
- Due to deficiency of Vit – B12
- Due to deficiency of Mutase enzymes
In both the cases, α – Methylmalonyl CoA is not converted to Succinyl Co A.
So, Methylmalonyl CoA is converted to Methyl malonic acid which is accumulated in blood and excreted through urine
═ Metabolic acidosis
Growth retardation are seen β-Oxidation in Peroxisomes : β-Oxidation in Peroxisomes Peroxisomes are cell organelles.
Initial steps of β-Oxidation for long chain Fatty acids takes place in Perosixomes.
FADH2 which are generated because of β-Oxidation in perosixomes does not enter into ETC to generate ATP
These FADH2 combine with O2 directly to generate H2O2
FADH2 + O2 FAD + H2O2
H2O2 H2O + ½ O2 Disorders related to β-Oxidation in Peroxisomes : Disorders related to β-Oxidation in Peroxisomes Zelweger syndrome:
Absence of Peroxisomes, so very long chain fatty acids are not oxidized.
Accumulation of very long chain fatty acids in tissues like brain, liver & Kidney.
This syndrome also known as Cerebrohepato renal syndrome. α – Oxidation of fatty acids : α – Oxidation of fatty acids Removal of one carbon unit at a time by oxidation of α – carbon of fatty acids is known as α – oxidation
α – oxidation takes place over the fatty acids where a group is attached on the β- carbon
Eg : Phytanic acid (derived from phytol present in chloroform,milk and animal fats)
α – oxidation takes place in endoplasmic reticulum,
Hydroxylation followed by oxidation of α-carbon .
Minor pathway requires cytochrome P450, NADPH & O2
doesn't produce energy Slide 39: Refsums disease:
Deficiency of Phytanic acid oxidase or α -hydroxylase
Phytanic acid accumulation in tissues.
Symptoms : Severe neurological disorders like polyneuropathy,retinitis pigmentosa and cerebellar ataxia. Slide 40: Thank you