Lipid metabolism 2 مفرغة.pdf

Lipid Metabolism FA fattyacids be Because Instructors : Professor Amein Al-Ali email: [email protected] Department of Clinical Biochemistry Thursday, December 7, 2023 Doneby Danaj Learning objectives At the completion of these lectures students should be able to: • Discuss the role of the lip...

Lipid Metabolism FA fattyacids be Because Instructors : Professor Amein Al-Ali email: [email protected] Department of Clinical Biochemistry Thursday, December 7, 2023 Doneby Danaj Learning objectives At the completion of these lectures students should be able to: • Discuss the role of the lipids in metabolisms • Discuss Lipogenesis & β oxidation pathways References: Life, The Science of Biology 9th ed Savada et al Biochemistry, Lippincott Thursday, December 7, 2023 08:06 removing é andconverted by FA carbonskeltonof FAintoCo2 β- Oxidation of fatty Acids (Mitochondria) occurs in mitochondria I B oxidation 21h 6 Go at 04 D g I so mitonhendria.no diet t.ws a Thursday, December 7, 2023 Presentation Fuel Molecules III title d Cakes a ftp.t 08:06 The Carnitine Shuttle Cytosol to Mitochondria ciEE ititransports.stemccarnitinesnutties  For the transport of long chain fatty acids, the fatty acid is first transferred to the small molecule, carnitine by carnitine palmitoyl CPT1 transferase 1 located in the outer mitochondrial membrane.  An acyl carnitine transporter or translocase in the inner mitochondrial to membrane then facilitates transfer of the fatty acid into the mitochondria , where CPT-11 regenerates the acyl CoA releasing free carnitine.  The carntine shuttle operates by an antiport mechanism in which free carnitine and acyl carnitine derivative move in opposite direction across the inner mitochondrial membrane.  The carnitine shuttle is inhibited by malonyl CoA after the ingestion of carbohydrate rich meals preventing the catabolism of newly synthesized fatty acids and favoring their export from the liver for storage in adipose tissue. acids a ttached carnitine When the fatty acid is transported into the mitochondria, CPT-1 acts on the acyl carnitine and facilitates the transfer of the fatty acid back to CoA, resulting in the regeneration of acyl CoA. This step allows the fatty acid to enter the mitochondrial metabolic pathways for energy production. As a consequence of this conversion, the carnitine molecule that was previously carrying the fatty acid is released, becoming "free carnitine" once again. Free carnitine can now be reused for the next round of fatty acid transport from the cytoplasm to the mitochondria. Thursday, December 7, 2023 Presentation Fuel Molecules III title 08:06 Carnitine shuttle 8319 1 angst in Acetyl CoA f JÉÉIiÉ Thursday, December 7, 2023 Presentation Fuel Molecules III title FromMED222 08:06 Oxidative Metabolism of Lipids -Oxidation of Fatty Acids occurs in the mitochondria 3 stages: 1. removal of 2 carbon units as acetyl CoA 2. acetyl CoA formed enters the citric acid cycle no I 3. reduced electron carriers (NADH & FADH2) transfer electrons to the electron transport chain to yield energy Thursday, December 7, 2023 Presentation Fuel Molecules III title m ic Isa about4 times whatweget Glucose from eachacetylCoAisentertheTCA ATP andcoand12 andconvertitintoH2O Baynes Fig 15.3 β- Oxidation Reactions 1  Two-carbon fragments are successively removed from the carboxyl end of the fatty acyl CoA, producing acetyl CoA, NADH, and FADH2.  Occurs in the matrix side of inner mitochondrial membrane.  Several enzymes collectively called fatty acid oxidase are found in mitochondrial matrix which catalyse the oxidation of fatty acyl CoA to acetyl CoA. 2 3  16:0 will need 7 cycles of β-oxidation  Inhibitor of β-oxidation is Malonyl CoA e β-oxidation consists of four basic reactions: 1. Dehydrogenation , 2. Hydration 3. Dehydrogenation, 4. Cleavage ADÉLIE Thursday, December 7, 2023 4 β- Oxidation Reactions ENERGY YIELD from fatty acid oxidation: The energy yield from the βoxidation pathway is high. For example, the oxidation of a molecule of palmitoyl CoA (C16) to CO2 and H2O yields 131 ATPs . C16 + 7FAD + 7NAD + 7CoA =8 acetyl CoA + 7FADH2 + 7NADH+ 7H+ HOW?? 16:0 has 7 cycles: 7 x35=35 ATP (which comes from NADH and FADH2) 1 FADH2 gives 2 ATP: 7x2=14 1NADH gives 3 ATP: 7 x 3= 21 Each acetyl CoA produces 12 ATP in the TCA cycle: 12 x 8 = 96 Total ATP formed is : 35 + 96 = 131 ATP Thursday, December 7, 2023 from only 1mole of palmiticacid Ketone Bodies The ketone bodies are acetoacetate, β-3hydroxybutyrate and acetone. Liver mitochondria have the capacity to convert acetyl CoA derived from fatty acid oxidation into ketone bodies. They are synthesized by the liver from acetyl CoA Thursday, December 7, 2023 0 0 42 4 Fi whenweneedenergyweuse fattyacidbutaswekno the soluble a cids blood fatty arenot inthe Asaresultotfhat Fattyacidaretransportedtoliverwhereitcanbeconvert to anewcompoundcalled ketonebodieswhich ff.fm Ketone Bodies BoxidationforFA a in livernottoproduce 2C energy but toproduce Keton bodies 2ActegleCoA ③ 4C 2C 6C STEITIA 4C Solublein blood Thursday, December 7, 2023 Acetoactyle C Aacetfle CoA HMECoA Ketone Bodies UTILIZATION BODIES: OF note KETONE Ketone bodies are important sources of energy for the peripheral tissues during fasting such as: Muscles Brain like thetimeuseketonebodies Allproduce e nergy to AE ni hypoglycemia Any fdthibodies toproduceenergy Thursday, December 7, 2023 i Ea.fia aii In normal person ill never haveaceton Thursday, December 7, 2023 P a inTissueBlood Presentation title of amount acetoacetate huge stimulate w hich of.PH lead win ttohelowering theconverte Ketone Bodies DIABETES When the rate of formation of ketone bodies is greater than the rate of their use, their levels begin to rise in the blood (Ketonemia) and eventually in the urine (ketonuria). These two conditions are seen most often in cases of uncontrolled, type 1 (insulin-dependent) diabetes mellitus. GAn increase in ketone bodies can also cause severe acidosis insulinGlucagon enter andstimulateittoketogenesisleadtohuge sincetheGlucagonsignal liver the a mountof bodies ketone acid are they sowhenitincrease itwwwthepHbecause t.gghytyqqffgyg fgfggg (ketoacidosis). Ketoacidosis may also be seen in cases of iii.it fasting . summara DMorstarvation ii During uncontrolled Thursday, December 7, 2023 i EEEE 08:06 Fate of Glycerol TAG fatty acids + glycerol fatintoglucosebutglucosecanconvert converted wecant intofat Isn'tfat_ • 95% energy: fatty acids • 5% energy: glycerol The energy in glycerol can be released via glycolysis and the citric acid cycle and used for gluconeogenesis P Thursday, December 7, 2023 Presentation Fuel Molecules III title glycolysisw.mg itupinto anucantake 08:06 Essential fatty Acids Arachidonic Acid is rapidly converted into: prostaglandins, prostacyclin and thromboxane. Him They control processes such as inflammation, blood flow, the formation of blood clots and the induction of labour. thromboxane is a potent vasoconstrictor and stimulus for platelet aggregation while prostacyclin produced by both vascular smooth muscle and endothelium that stimulates vasodilation. Thursday, December 7, 2023 essential three The acid fatty diet our takein thatweshould ask.ws Presentation title Cholesterol Meatbolism Most cholesterol is in free form and can be absorbed readily from diet. All the dietary cholesterol is incorporated into miscelles (deestered in miscelles) and then incorporated into chylomicrons, which transport cholesterol into plasma and eventually deposits in the liver. Almost all tissues are able to synthesize cholesterol but more than 90% of indigenous cholesterol is made by liver and intestinal mucosa. All the synthetic reactions occur in the cytoplasmic compartment of the cell and all the enzymes are in the endoplasmic reticulum. 12/7/2023 Thursday, December 7, 2023 Presentation title Transformations of Cholesterol: Steroid Hormones OH CH3 O O OH HO CH3 O HO O Cortisol Cholesterol Progesterone OH OH OH O Testosterone HO CH 2 Estradiol 12/7/2023 Thursday, December 7, 2023 HO OH Vitamin D Presentation title mimportant there FI a iisestn 12/7/2023 Thursday, December 7, 2023 Presentation title R.EE EaEEi The drug that inhibits HMG-CoA reductase is commonly known as a statin. Statins are a class of medications used to lower cholesterol levels in the blood by blocking the action of HMG-CoA reductase, which is an enzyme involved in the production of cholesterol in the liver. By inhibiting this enzyme, statins reduce the production of cholesterol and ultimately help lower the levels of low-density lipoprotein (LDL) cholesterol, often referred to as "bad" cholesterol. 12/7/2023 Thursday, December 7, 2023 Presentation title 08:06 SIDS (Sudden Infant Death Syndrome) • • • • • • A disorder due to blockade in Beta- Oxidation SIDS is unexpected death of healthy infants usually overnight. The real cause of SIDS is not known. CaCa But at least 10% is due to deficiency of medium chain acyl CoA dehydrogenase. DeficiencyinthefirstenzymeofBoxidation The occurrence of SIDS is explained that the glucose is the principal source of energy soon after eating or feeding babies. After a few hours, the glucose level decreases and the rate of fatty acid oxidation must increase to meet the energy needs. The sudden death in infants is due to a blockade in beta- oxidation caused by a deficiency in medium chain acyl CoA dehydrogenase (MCAD). Thursday, December 7, 2023 Presentation Fuel Molecules III title 08:06 Zellweger Syndrome  It is inherited in an autosomal recessive manner  Syndrome typically appear during the newborn period Duringthef month and may include poor muscle tone (hypotonia), poor feeding, seizures, hearing loss, vision loss, distinctive facial features, and skeletal abnormalities. Children with Zellweger syndrome usually do not survive beyond the first year of life  This is rare disorder characterized by the absence of peroxisomes in almost all the tissue (12 different genes,70% have mutation in PEX1 gene). 1 forfattyacidsshorteningeney is  AS a result , the long chain fatty acids are not oxidized .  They accumulate in tissues, particularly in brain, liver and kidney. which responsible Thursday, December 7, 2023 Presentation Fuel Molecules III title Thank You Thursday, December 7, 2023