67. Triglyceride in Muscle. Insulin resistance and intramyocellular triglycerides Muscle: insulin-responsive glucose disposal, glucose flux 의 약 80% 나타남.

Slides:



Advertisements
Similar presentations
This class Organization of cellular energy metabolism: entry of carbon fuels transport within cell metabolic interconversions in cytosol transport and.
Advertisements

Fatty Acid Metabolism. Introduction of Clinical Case n 10 m.o. girl –Overnight fast, morning seizures & coma –[glu] = 20mg/dl –iv glucose, improves rapidly.
LIPOLYSIS: FAT OXIDATION & KETONES BIOC DR. TISCHLER LECTURE 33.
Integration & Hormone Regulation Integration Branchpoints in metabolism where metabolites can go several directions 1. Glucose 6-phosphate Energy needed.
Acetyl-CoA Carboxylase-A New Target in the Fight against Obesity Naida Idrizovic.
Fatty Acid Synthesis Fatty Acid Synthase Acetyl-CoA serves as a primer
Synthesis of Triglycerides
Cell Injury and Cell Death
Fuel for Exercise: Bioenergetics and Muscle Metabolism
Lipid Metabolism During Exercise. Plasma Free Fatty Acid Metabolism Plasma FFA during exercise result primarily from mobilized lipid stores in adipose.
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings  High-energy phosphate groups are transferred directly from phosphorylated substrates.
Lipid Metabolism 1: Overview of lipid transport in animals, fatty acid oxidation, ketogenesis in liver mitochondria Bioc 460 Spring Lecture 35 (Miesfeld)
Homeostatic Control of Metabolism
Physiological role of insulin Release of insulin by beta cells –Response to elevated blood glucose level –Effects of insulin Somewhat global Major effects.
Overview of catabolic pathways. Chapter 16 - Lipid Metabolism Triacylglycerols and glycogen are the two major forms of stored energy in vertebrates Glycogen.
Cellular Biochemistry and Metabolism (CLS 333 ) Dr. Samah Kotb Nasr Eldeen.
Metabolism Chapter 24 Biology Metabolism overview 1. Metabolism: – Anabolic and Catabolic Reactions 2. Cell respiration -catabolic reaction 3. Metabolic.
Absorptive (fed) state
Goals: 1) Understand the mechanism for ↑LDL in Type II diabetes 2) Having previously established the link between endothelial cell damage (loss of inhibitory.
Lipids in the body Functions 1. Membrane component 2. Thermal insulation and mechanical protection 3. Metabolic regulator 4. Energy store -90% of an adipocyte.
Macronutrient Metabolism in Exercise and Training
The pathophysiology of type 2 diabetes Jean GIRARD Institut Cochin Paris.
Nutrient Role in Bioenergetics Chapter 4 Part 2. Bioenergetics-Glycolysis  Carbohydrates primary function  Energy for cellular work.  Breakdown of.
Chapter 2 Chapter 2 Cardiac Metabolism in Health and Disease © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular.
Metabolic effects of Insulin and Glucagon Metabolism in the Well fed state Metabolism in the Starvation and Diabetes Mellitus Integration of Metabolism.
Fatty Acid Handling Beta-oxidation FA transport
Ch 9. Lipotoxicity 정혜승. Introduction Definition of lipotoxicity : excess TG in nonadipocytes(=steatosis) → adverse effects on function or.
Integration of biochemical and physiologic effects of insulin on the control of blood glucose concentrations June 1st, 2004.
Carbohydrates as Energy Sources. Na + /K + pump is key to SGLT1 function; exchanges Na + for /K + to maintain the gradient; uses energy (i.e., ATPase);
Post-Absorptive Lipid Metabolism
Lipolysis. Largest storage form of energy Provides energy at the slowest rate Stored: –adipose tissue –muscle –Brain, CNS, abdomen, etc. Use of lipids.
Alterations of Lipid Metabolism in Diabetes Mellitus
Copyright © 2006 Lippincott Williams & Wilkins. Fundamentals of Human Energy Transfer Chapter 5 Section 3: Energy Transfer.
AMP Activated Protein Kinase (AMPK)
Mechanisms of Myocardial Contraction Dr. B. Tuana.
Physiology: Carbohydrate Metabolism. The pancreas the gland responsible. Insulin production and secretion. Insulin receptors. Glucose transporters. Insulin.
Selected Hormonal Issues Relating to Exercise and Substrate Use.
Coordinated regulation of glycolysis/gluconeogenesis.
Transduction of Extracellular Signals Specific receptors in plasma membranes respond to external chemicals (ligands) that cannot cross the membrane: hormones,
Integration of Metabolism Lecturer of Biochemistry
GLYCOLYSIS Learning objectives: List the enzymes and intermediates involved in glycolysis List the irreversible and regulated steps of glycolysis Discuss.
Cell Metabolism. BIG PICTURE BIG PICTURE The sun provides the energy that powers all life The sun provides the energy that powers all life Animals depend.
Fatty Acid Metabolism 1. Fatty acid synthesis.
Lipid Metabolism During Exercise. Introduction 1.) Energy Density 2.) Polar explorers/sled dogs American Indians (pemican) 3.) Migrating fish and birds.
Date of download: 7/2/2016 Copyright © The American College of Cardiology. All rights reserved. From: The Adrenergic-Fatty Acid Load in Heart Failure J.
Protein Receptors & Signal Transduction
Hormonal regulation of lipid metabolism
PPAR δ : a dragger in the heart of the metabolic syndrome J.Clin.Invest.116:590~597(2006) R3 Song Se-bin Grant D. Barish, Vihang A.Narkar, and Ronald M.Evans.
Hormonal regulation of lipid metabolism
Unit 1 Lesson 6 Activity 3- Insulin and the Human Body
Lipid metabolism.
Obtaining Energy from Food
The Endocrine Pancreas
OXIDATION OF FATTY ACIDS
Diabetes Mellitus.
Ex Nutr c7-fat.
Normal And Abnormal Cardiac Muscle Metabolism
FIGURE 14-9 Effect of type 1 diabetes on carbohydrate and fat metabolism in an adipocyte. Normally, insulin triggers the insertion of GLUT4 transporters.
Metabolism of cardiac muscle
Insulin Beef Drugbank ID : DB09456 Molecular Weight (Daltons) :5733.5
NASH: a mitochondrial disease
Volume 11, Issue 5, Pages (May 2010)
ATP and Energy Pathways
Figure 2 Lipid metabolism and metabolism-disrupting chemicals.
Varman T. Samuel, Gerald I. Shulman  Cell Metabolism 
Volume 159, Issue 6, Pages (December 2014)
Protein Tyrosine Phosphatase 1B
Mechanisms for Insulin Resistance: Common Threads and Missing Links
Volume 104, Issue 4, Pages (February 2001)
The Endocrine Pancreas
Presentation transcript:

67. Triglyceride in Muscle

Insulin resistance and intramyocellular triglycerides Muscle: insulin-responsive glucose disposal, glucose flux 의 약 80% 나타남. Muscle 에서의 insulin action 결함 : glucose uptake, phosphorylation (oxidation 에 의한 disposal, glycogen 으 로 저장 ) Fatty acids (circulating triglycerides-VLDLs and chylomicrons, bound to plasma albumin): directional transport 통해 myocytes 에 의해 흡수됨. Intramyocellular triglycerides 와 균형을 이룸. - intramyocellular lipid store : rapid turnover 로 인해 높은 activity, adipocyte differentiation related protein (ADRP) 같은 specific protein 에 bound 된 상태. - In contrast, adipocytes 내에 저장되어있는 triglycerides: 느린 속도의 turnover, 상대적으로 inactive.

Proton magnetic resonance spectroscopy Proton magnetic resonance spectroscopy (H-MRS) : powerful new method – muscular lipid store 평가, intramyocellular lipid (IMCL) pool 측정. Myocytes 내의 lipid: small (~0.2um) lipid droplets 안에 저 장 Adipocytes 안에 저장된 lipid: linear array 형태 MRS: 극도의 magnetic field 영향 아래에 있을 때, 본질적 인 magnetic moment 를 가진 nuclei 를 detect. 나타나는 wave frequency 가 특이적 정보 제공 – nucleus 에 대한, 결합되어 있는 chemical compound 에 대한.

How does increased intracellular lipid cause insulin resistance? 다량의 fatty acids 있을 때, Glucose oxidation 감소 : 짧은 시간 내에 glucose uptake, glycogen 전환에는 영향 못 미 침.  긴 기간 동안 다른 mechanism 이 glucose uptake 와 저 장을 악화시킬 것임.

Long-chain acyl-CoA (LCACoA): insulin-resistant animal(human) 에서 증가, weight loss 또는 leptin treatment 하면 감소. LCACoA  hexokinase IV 억제 (muscle intracellular glucose metabolism 의 첫번째 enzyme) LCACoA  다양한 transcription factors (HNF-4, Fad R) 와 bind.  but, muscle gene transcription 에 직접적인 영 향은 없음. LCACoA  insulin-signaling cascade 를 방해. : 직간접적으로 muscle 에 있는 protein kinase C (PKC) 의 다양한 isoform 이 활성화 됨  insulin receptor substrate 1 (IRS-1) 의 tyrosine phosphorylation 이 block  downstream activation 억제  glycogen synthase activation 억제 (plasma membrane surface 로의 glucose transporter4 이동 억제 등.)

Why do lipids accumulate in skeletal muscle? The reverse randle cycle 영양 과다  과도한 lipid supply, muscle 같은 조직에 오 랜 시간 accumulate (also liver and pancreatic  –cells) Fatty acid disposal : CPT-I/malonyl-CoA systemp 의해 조절 (Fig. 67.6) CPT-I : outer mitochondrial membrane 에 위치,  –oxidation 을 위해 mitochondria 로 들어오는 fatty acid 를 rate-controlling.

Carbohydrate 섭취, insulin 증가 등  muscle acetyl-CoA carboxylase (ACC-2) 활성  malonyl-CoA 형성 malonyl-CoA  CPT-I 활성 억제, mitochondria 로 많은 LCACoA 들어오는 것 막음 Nutrient 감소, insulin 감소  ACC-2 억제  malonyl- CoA level 감소  CPT-I 활성, fatty acids 가  –oxidation 과정

Adenosine monophosphate-activated protein kinase (AMPK) : hypoxia, exercise/contraction 같은 cellular stress 에 의해 활성화됨. AMPK activation (ACC-2 의 억제와 함께 )  malonyl-CoA decarboxylase (MCD) 를 phosphorylate and activate, malonyl-CoA level 낮춤.

Paradoxical increases in intramyocellular lipid with normal/increased insulin sensitivity Physical training  IMCL 증가, muscle oxidative capacity 증가. fatty acid uptake 관련 enzyme (lipoprotein lipase), fatty acid oxidation  strongly induced  fuel substrates 의 효과적인 전달 위해. Aerobic training 이 어떻게 insulin sensitivity 와 triglyceride 저장을 모두 증가시키는지 : mystery.  가능성 : small lipid droplet, mitochondria 에 근접  lipolyzed fatty acids 가 oxidation 위한 channel 이 됨.  반복적인 triglycerides 의 저장과 분해  LCACoA 낮은 농도.

Is fatty acid oxidation compromised in insulin resistant states? Fat oxidation 결함  muscle 에서 lipid accumulation, insulin resistance : Glucose 와 insulin 의 acute exposure  fat oxidation block, muscle malonyl-CoA 증가. RQ (fat oxidation 의 불가능 정도 측정 ) 증가 Fat oxidation 능력의 감소  weight gain, insulin resistance  type 2 diabetes

The paradox of high intramyocellular lipids: A possible explanation Lipid 공급과 소비가 균 형  fatty acyl-CoA (FA-CoA): normal level 운동시, FFA 공급 증가 ( 저장과 회복 위한 enzymatic machinery) 초과 공급  FA-CoA level 증가 (TG level 의 증가로 새로운 steady state 에 도달할 때까지 ) CPT-I 의 억제  intramyocellular lipid 증가, insulin resistance

CPT-I/malonyl-CoA pathway 의 결함  lipid 공급 초과  triglycerides 축적 triglycerides 축적, LCACoA 활성  muscle 에서의 insulin resistance, pancreatic  -cell 에서 insulin 의 과다분비,  - cell 결함, diabetes 등의 과정 진행. Obese insulin-resistance, obese diabetic subjects 에서 basally fat oxidization 감소 : muscle CPT-I 과 oxidative enzyme activity 감소, FABP protein 증가.

Oxidative capacity 의 결함에 대한 설명 : insulin-resistant and insulin-sensitive groups 사이의 fiber type 에 따른 차 이  type I fiber : 많은 mitochondria 가짐  더 좋은 oxidative capacity, type IIa 와 IIb fiber 와 비교하면 더 좋은 insulin 반응.  succinyl dehydrogenase (SDH) : mitochondrial oxidative marker enzyme  obese 와 diabetic group 에서 감소 경향  SDH 와 intramyocellular lipid 의 비율 (oil red-O staining 으로써 ) : control 보다, obese 와 diabetic group 에서 모든 fiber type 이 감소 함.

Lipotoxiciity and the long-term implications of impaired fatty acid oxidation Muscle oxidative capacity 감소  mitochondrial number 또는 function 감소 ?  이를 평가하기 위해, NADH:O 2 oxidoreductase activity 측정 (mitochondrial electron transport chain 의 전체적인 활성 평가하는 enzyme)  lean>obese>diabetic 순서로 감소됨  obese 와 diabtic group 에서, vacuolization, mitochondrial fragment, smaller mitochondrial size 결함.  NADH:O 2 oxidoreductase activity 감소와 mitochondrial size 감소 는 insulin sensitivity 와 관련.  이러한 결함 : lipid 축적 증가, 과도한 lipid 저장에 따른 mitochondrial damage.

Lipotoxic heart disease: (cardiomyocyte specific acyl- CoA synthase 가 overexpress 되는 transgenic mouse model 에서 ) intracardiac triglyceride 축적, apoptosis cascade 유도, 점진적인 heart failure 나타남. Intracellular triglyceride 저장이 cell 의 oxidative capacity 넘어가면  과도한 triglyceride 는 ceramide 로 변환  nitric oxide synthase 유도, oxidative stress pathway 유도  hypertrophy, apoptosis 증가, cardiac 수축성 감소.

Conclusion Muscle triglyceride  intracellular lipid metabolism  H-MRS 등의 새로운 방법을 통해 설명됨 : intramyocellular lipid turnover controlling mechanism, insulin resistance 와의 관계 IMCL 저장 증가  aerobic capacity 또한 증가되 어야 함.  Aerobic capacity 감소  IMCL : insulin-resistant state 위한 중요한 marker