Tissue Metabolism - L12 - 10/02

What are some fat depots in the human body?
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1. Fed State - Insulin Release > Liver regulates blood glucose by taking up glucose and making glycogen and FA's (> TG > VLDL > storage in adipose) > decrease in blood glucose

2. Fasted State - Glucagon release > Liver regulates blood glucose by glycogenolysis and gluconeogenesis (uses glycerol from fat, lactate from RBC, and AA's from muscle) > synthesized glucose released into the blood for RBC and brain use

3. Glucose-6-P in liver can
- turn into glucose > glycogen
- Pentose phosphate pathway
- glycolysis
- turn into glucose > blood glucose
1. Albumin is a non specific blood transport protein (made by the liver) for steroid hormones, FAs, hydrophobic vitamins and drugs

Hypoproteinemia > edema (swelling) due to decrease protein-mediated osmotic pressure in the blood
- Ex: kwashiorkor syndrome, cirrhotic liver damage

2. Clotting factors

3. Glycoproteins function to inhibit proteases, acute phase proteins in immune response, secretoguges (induce secretion) for hormone release
FA metabolism during overnight fast PPAR knockoutFA = major fuel during overnight fast - Primarily long chain FA during fasting (from adipose) PPAR regulates long chain FA oxidation. Knockout > fatty liver in fasted stateMetabolism of lipids in liver diseaseReduced LCAT levels (enzyme that esterifies free cholesterol so that its activated to make lipoproteins) > More free cholesterol > less Lipoproteins (LPL, HTGL = peripheral lipase) > elevated TG in blood ↓CE + ↑TG = abnormal LDL composition Altered ↑ HDL3: HDL2 ratio (more atherogenic) In severe liver disease may have impaired VLDL production Elevated NEFA due to ↓ glucose output (↑ lipolysis)Amino Acid MetabolismPrimary site of a.a. metabolism occurs in the liver - Can metabolize all amino acids (Except: BCAAs-used for protein synthesis) Urea Cycle to rid toxic ammonia Protein SynthesisAmino Acid metabolism in liver diseaseElevated amino acid levels in the blood since liver is the primary site of AA metabolism (but its defective so no uptake) > Decreased urea production > hyperammonemia Cirrhotic Pts: Especially elevated Tyr, Phe, Trp, Met, yet lower levels of BCAAs.Liver synthesis of Nitrogen-Containing CompoundsLiver Xenobiotic DetoxificationExcretes products without nutritional value & potential toxicity Phase 1: Modification to prep for phase 2 (Primary metabolite) Phase 2: Rxns conjugate a negatively charged group to promote excretion (Secondary Metabolite)Cytochrome P450 Enzymes Function, Key component, examplesFunction Family of monooxygenase enzymes (found in smooth ER) that introduce an oxygen into a molecules, producing a reactive free radical intermediate. Key Component NADPH-cytP450 oxidoreductase (assuming it neutralizes the intermediate) Examples - CYP3A4 is the most common - CYP2E1: Acetaminophen can be detoxified through 3 different pathways, one of which uses CYP2E1 creating a toxic compound (NAPQI). CYP2E1 activity is increased with ethanol use (this is why you aren't supposed to take drugs with medicine)Ethanol MetabolismAlcohol and aldehyde dehydrogenases oxidize ethanol in a two-step process to produce acetate and 2 mol of NADH Increasing [NADH] inhibits β oxidation of FAs. Body will result to KBs instead because can't oxidize FAAlcohol Abuse and Fatty LiverEthanol metabolism makes hella NADH - FA metabolism altered (NADH inhibits b-oxidation = less oxidation, more synthesis) - Ketoacidosis (NADH inhibits TCA so Acetyl-CoA > KBs) - Lactic acidosis (NADH shifts LDH reaction towards lactate formation... LDH reaction occurs in RBC after glycolysis-turns Pyruvate > Lactate using NADH) - Hypoglycemia during fasting b/c Pyruvate use in LDH rxn takes it away from gluconeogenesis - Hyperglycemia in fed state Glycolysis inhibition > no glucose breakdown > high blood glucose levels Chronic effects: - Fatty liver (FA oxidation inhibited, stimulates TG synthesis) & hyperlipidemia - Hepatitis (increased oxidative species cause damage) - CirrhosisDevelopment of alcohol-induced hepatitisElevated ethanol metabolism intermediate: Acetaldehyde - Acetaldehyde can bind with amino acids impairs protein synthesis and secretion - Acetaldehyde can bind to glutathione or induce MEOS > ↑ ROS > ↑ Lipid peroxidation & cell damage - Mitochondrial damage inhibits ETC, which decreases acetaldehyde oxidation - Microtubule adduction results in damage that increases VLDL and protein accumulation - Cell damage > swelling > release of hepatic enzymes ALT & AST (Indicator of liver damage)Non-alcoholic fatty liver disease (NAFLD)- Hepatic steatosis: accumulation of fat in liver (when excessive alcohol consumption is ruled out) - Non-Alcoholic Steatohepatitis (NASH): Accumulation of fat in liver is combined w/ inflammation and cell damage - Fibrosis: scarring in an inflamed liver; 4 stages based on extent and distribution of scarring - Cirrhosis: Late stage of chronic liver disease marked by nodules of damaged liver cells surrounded by scarring Factors that contribute to NAFLD - Hyperinsulinemia - High Fat Diet - Inflammatory response (TNF-α & IL-6)Signs of liver damage- ↑ALT & AST; may have ↑ [a.a.] - inefficient bilirubin glucuronidation > jaundice - liver not producing enough clotting factors > prolonged clotting times - Edema (liver not producing enough albumin) - less urea > excess ammonia > encephalopathy ↑ ALP & GGT may indicate some liver diseasesCirrhosis & ManagementClinical Presentation - Jaundice - Thin walled varices (from shunting portal blood to liver) > varices may rupture causing bleeding - Increased ammonia in blood - Hepatic encephalopathy Management - Irreversible in later stages - Alcohol abstinence (avoiding hepatotoxins) - Management of symptoms and prevention of complications3 types of muscle tissueSkeletal muscle - Striated, multinucleated, long fibers - Attach to skeleton - Voluntary contraction - Different fiber types Smooth muscle - Not striated, mononucleated - Involuntary contraction Cardiac muscle - Striated, intercalated disks - Involuntary contractionSkeletal Muscle Fiber TypesType I - Slow Oxidative (SO) Fibers - Lots of mitochondria, myoglobin (MB) - Relatively resistant to fatigue - Relatively low glycogen content - Develop force slowly, maintain contractions longer - Prominent in postural muscles Type IIb - Fast glycolytic (FG) fibers - Few mitochondria, Mb - Prone to fatigue - Rich in glycogen - Develop greater force, contractions occur more rapidly - Prominent in large muscles of limbsDistinguish between muscle fuel usage based on one's state (fed or fasted)Fed State - Glucose (little FA) Brief Fast - KB (little FA) - Glucose - Little glycogen - Prolonged fast - FA Exercise/ Increased demand - Glucose - FA - Muscle Glycogen - KBCori CycleLactate produced by anaerobic glycolysis can be used for gluconeogenesis in liver (Requires ATP)Evaluate the use of creatine kinase and adenylate kinase in skeletal muscle ATP generation.Creatine kinase makes Creatine Phosphate which allows for rapid ATP generation via adenylate kinase. AMP products used to stimulate glycogenolysis and glycolysis. - ATP + Creatine (Creatine Kinase)> Phosphocreatine + ADP - 2 ADP (Adenylate kinase)> ATP + AMPHow is creatinine formed? Purpose?Spontaneous formation of creatinine - Creatinine released from skeletal muscles at steady rate, proportional to muscle mass - Excreted in urine - Can be used to determine concentration of other molecules excreted in urine - Elevated in blood suggests impaired renal functionFuel use at rest and during prolong exercise- Glycogen levels used mostly during short duration of intense exercise - Shifts to FAs over prolonged period of time & some blood glucoseMuscle FatiguePossible contributors: - Muscle glycogen depletion - Impaired rate of glycolysis - Na+/ K+ ATPase - Exercise-induced acidosis - Lactate accumulation & osmotic gradient - Dehydration - Percentage of type II skeletal muscle fibers Depends on: - Type, duration, and intensity of activity - Type of contraction - Muscle fiber type - Level of fitnessDiminished Blood Flow to cardiac tissueWhich type of muscle cell(s): 1. Is striated? 2. Is subject to involuntary contraction? 3. Is not striated and is subject to involuntary contraction? 4. Is multinucleated? 5. Has intercalated disks? 6. Exists as muscle fibers?1. Skeletal and Cardiac 2. Cardiac and smooth 3. Smooth 4. Skeletal 5. Cardiac 6. SkeletalWhich type of muscle fiber: 1. Has more mitochondria? 2. Has more myoglobin? 3. Can generate more force in a short amount of time? 4. Is more glycogen-rich? 5. Is more resistant to fatigue? 6. Is more prominent in the quadriceps and biceps? 7. Is more prominent in muscles of the back?1. slow twitch (type 1) 2. slow twitch (type 1) 3. fast twitch (type 2b) 4. fast twitch (type 2b) 5. slow twitch (type 1) 6. fast twitch (type 2b) 7. slow twitch (type 1)1. What is the function of creatine phosphate? 2. What is creatinine release proportional to? 3. Elevated creatinine levels in blood? 4. Low creatinine levels in urine? 5. High creatinine levels in urine?1. rapid ATP generation via adenylate kinase 2. Muscle mass 3. Kidney damage 4. Kidney damage 5. Muscle damage