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1 2013 W. H. Freeman and Company 17 Fatty Acid Catabolism

2 Fatty Acid Catabolism Key topics: How fats are digested in animals How fats are mobilized and transported in tissues How fats are oxidized How ketone bodies are produced

3 Glycogen Glycogenolysis Glycogenesis Glucose Insulin Triacyglycerol Esterification Lipolysis Fatty acid Glucagon Gluconeogenesis Glycolysis Lipogenesis Pyruvate Acetyl CoA β-oxidation TCA Mt Amino Acid NADH Amino Acid ATP

4 Oxidation of fatty acids is a major energy source in many organisms About one third of our energy needs comes from dietary triacylglycerols : 40% 식이 >>> 지질 30% 이하추천 About 80% of energy needs of mammalian heart and liver are met by oxidation of fatty acids ( 휴식근육 ) Many hibernating animals, such as grizzly bears, rely almost exclusively on fats as their source of energy

5 Fats provide efficient fuel storage The advantage of fats over polysaccharides: Fatty acids carry more energy per carbon because they are more reduced Fatty acids carry less water along because they are nonpolar Glucose and glycogen are for short term energy needs, quick delivery Fats are for long term (months) energy needs, good storage, slow delivery

6 Fatty acid oxidation 지방산의소화, 동원그리고운반 1. 식이성지방 1) 흡수과정 ( 소장에서 흡수 ) 1 담즙산염의식이성지방유화시켜 micelle 생성 2TG 분해 3 지방산, 분해생성물흡수 : 장점막에서 TG로변환 4 TG (+cholesterol+apolipoprotein) 가 chylomicron 생성 5 chylomicron이조직으로운반 (via 림프계 & 혈류 ) 6 lipoprotein lipase가지방산과 glycerol 유리 7 지방산이세포로들어감 8 glycerol이해당과정으로들어감 9 지방산-산화, 저장

7 Dietary fatty acids are absorbed in the vertebrate small intestine

8 Lipids are transported in the blood as chylomicrons

9 2) Lipoprotein 1 VLDL (very low density lipoprotein) 2 VHDL (very high density lipoprotein) 3) Hormone-sensitive TG lipase - ester결합의가수분해촉매 * 저혈당 Epinephrine 및 Glucagon이 adenylate cyclase 활성화 camp 생성 camp-dependent protein kinase(pka) 가 TG Lipase를인산화하여활성화시킴 FA방출 혈류내혈청 albumin과지방산결합 : 지방조직에저장된 TG의동원

10 Hormones trigger mobilization of stored triacylglycerols Epinephrine

11 Hydrolysis of fats yields fatty acids and glycerol Hydrolysis of triacylglycerols is catalyzed by lipases Some lipases are regulated by hormones glucagon and epinephrine Epinephrine means: We need energy now Glucagon means: We are out of glucose

13 Glycerol from fats enters glycolysis Glycerol kinase activates glycerol at the expense of ATP Subsequent reactions recover more than enough ATP to cover this cost Allows limited anaerobic catabolismof fats

Overview of metaboilsm 단백질합성 Glycogenesis Glycogenolysis S70S6K mtor Glu Insulin Glucagon Epinephrine F-1,6-bisphosphatase Phosphofructokinase Glut2,4 IR IRS GProtein F-6-P Glu PI

14 Overview of metaboilsm 단백질합성 Glycogenesis Glycogenolysis S70S6K mtor Glu Insulin Glucagon Epinephrine F-1,6-bisphosphatase Phosphofructokinase Glut2,4 IR IRS GProtein F-6-P Glu PI 3 K GSK3β Akt Phosphoenolpyruvate kinase((pepck) FOXO1,HNF-4 GS SREBP-1,2 Glycogen 합성 camp PKA PGC1 α PPAR α/β Pyr dehydrogenase Chol synthesis HMG-CoA reductase Cholesterol ChREBP

15 Blood Cell Glu Glut2, 4 FFA FATP gluconeogenesis Pyr glycolysis FFA ACS Acyl CoA CPTⅠ Chol Mt Ketone body Pyr Pyr dehydrogenase CPTⅡ FA synthesis HMG-CoA Acetyl CoA β-oxidation Chol synthesis Chol TCA cycle Acetyl CoA ATP

16 2. 지방산의활성화와운반 1) 지방산 + CoA + ATP 지방산활성화 (acyl-coa) + AMP + PP i O ATP R-C 2P i 실제로 2개의 ATP 필요 S-CoA by fatty acyl-coa synthetase 2) Mitochondria(Mt) 내로지방산의도입 acyl CoA 가 carnitine 의 hydroxy 기와 ester 교환반응 (carnitine acyltransferaseⅠ(cpt1) 에의해촉매 ) 지방산 acyl-carnitine ester 가 Mt. 내막을가로질러 matrix 로이동 지방산 acyl 기가 carnitine 으로부터 Mt. 내의 CoA 로옮겨짐 *carnitine acyltransferaseⅡ(carnitine palmitoyl transferase(cpt2)) 에의해 carnitine은 Mt. 의내막외막사이로다시들어감 O R-C carnitine carnitine S-CoA Ⅰ Ⅱ O acyl CoA-SH R-C carnitine carnitine R-C O CoA-SH S-CoA -oxidation <outer membrane> <inner Membrane> <matrix>

17 Transport or attachment to phospholipids requires conversion to fatty acyl CoA fatty acyl CoA synthetase

18 Fatty Acid Transport into Mitochondria Fats are degraded into fatty acids and glycerol in the cytoplasm of adipocytes Fatty acids are transported to other tissues for fuel oxidation of fatty acids occurs in mitochondria Small (< 12 carbons) fatty acids diffuse freely across mitochondrial membranes Larger fatty acids (most free fatty acids) are transported via acyl carnitine/carnitine transporter

19 Carnitine shuttles fatty acids into the mitochondrial matrix

20 Acyl Carnitine/Carnitine Transport

21 Stages of Fatty Acid Oxidation Stage 1 consists of oxidative conversion of two carbon units into acetyl CoA via β oxidation with concomitant generation of NADH and FADH 2 involves oxidation of β carbon to thioester of fatty acyl CoA Stage 2 involves oxidation of acetyl CoA into CO 2 via citric acid cycle with concomitant generation NADH and FADH 2 Stage 3 generates ATP from NADH and FADH 2 via the respiratory chain

22 Stages of Fatty Acid Oxidation

23 oxidation 지방산산화의단계 1 -산화 : 지방산 acyl chain의연속적산화 2-탄소단위인 acetyl-coa 생성 2 acetyl-coa의 acetyl잔기의산화 : TCA cycle CO 2 3 2에서생긴 NADH, FADH2가호흡사슬에전자전달 ADP + P i ATP / 2H + + ½O 2 H 2 O 1) -oxidation 경로 (palmitoyl-coa) (C16)R-CH 2 CH 2 CH 2 C-S-CoA palmitoyl-coa + 7CoA + 7O P i + 28ADP 8 acetyl-coa + 28ATP + 7H 2 O 실제 palmitoyl-coa의 ATP 수율 ( -oxidation) 28개 <( )ⅹ7> +<(TCA cycle) > 80개- 2개 ( 지방산활성화 ) =106개 2) 불포화지방산의산화 1 Monounsaturated FA(Oleoyl-CoA 9): Enoyl-CoA isomerase 필요 double bond 재배치, cis이성질체를 Trans 로바꾸어줌 2 Polyunsaturated FA(Linoleoyl-CoA 9,12 ): Enoyl-CoA isomerase & 2,4-dienoyl-CoA reductase

24 The Oxidation Pathway Each pass removes one acetyl moiety in the form of acetyl CoA.

25 Step 1: Dehydrogenation of Alkane to Alkene Catalyzed by isoforms of acyl CoA dehydrogenase (AD) on the inner mitochondrial membrane Very long chain AD (12 18 carbons) Medium chain AD (4 14 carbons): 결손시지방간, 저혈당증, 혼수 ( 미국, 유럽다 ) Short chain AD (4 8 carbons) Results in trans double bond, different from naturally occurring unsaturated fatty acids Analogous to succinate dehydrogenase reaction in the citric acid cycle Electrons from bound FAD transferred directly to the electrontransport chain via electron transferring flavoprotein (ETF)

Lehninger Principles of Biochemistry 5/e

David L. Nelson and Michael M. Cox LEHNINGER PRINCIPLES OF BIOCHEMISTRY Fifth Edition CHAPTER 17 Fatty Acid Catabolism 2008 W. H. Freeman and Company Chap. 17. Fatty acid oxidation 지방산의소화, 동원그리고운반 1. 식이성지방