Liver - Glucose Regulation, Fat metabolism

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GLUCOSE REGULATION
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GLUCOSE REGULATION
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Describe the absorptive state
• Ingested nutrients in the GI tract absorbed into blood
• some CATABOLISED and used in metabolism
• excess converted + stored for later use

In absorptive state
glucose → metabolised to generate ATP
glucose → glycogen store
amino acids → proteins
FAs + glycerol → lipids
Describe the post-absorptive state
• GI track empty of nutrients
• Energy/nutrient stores MUST supply the energy needs of the body
In the post-absorptive state, glucose levels must be regulated.

Why?
• Glucose is no longer available for absorption from GI tract

• But plasma conc. of glucose MUST be maintained as the CNS relies on glucose for fuel

• Glucose must come from other sources
3 sources of glucose in post-absorptive state
1. Glycogen (glycogenolysis)

2. Lipids (gluconeogenesis)

3. Protein (gluconeogenesis)
GLYCOGENOLYSIS

• Where are body stores of glycogen
• Broken down to which monomer
• Liver & skeletal muscle

• Glucose-6-phosphate (not straight to glucose!!!)
Liver and skeletal muscle - does one contain more glycogen?
Both contain SAME amounts of glycogen
Hepatic glycogenolysis vs. skeletal muscle
Glycogen → glucose-6-phosphate

Liver:
• Glucose-6P ENZYMATICALLY converted to glucose
• this glucose → blood

Skeletal muscle:
• Do not have enzymes for conversion of glucose-6P to glucose
• Glucose-6P undergoes GLYCOLYSIS → pyruvate, ATP, lactate
Body's FIRST LINE OF DEFENCE in maintaining plasma blood glucose conc. within homeostatic range:
• Hepatic glycogenolysis

• Begins within SECONDS of appropriate stimulus

• Such as SYMPATHETIC STIMULATION
However, the hepatic glycogen can only supply body's requirements for ...

Thus, glycogenolysis also occurs in ...
several hours before depletion

skeletal muscles (contain same amount of glycogen as liver)
Muscle glycogen is NOT a source of...blood glucoseGlycogenolysis & subsequent ... in muscle forms ... Fate of each product ...Glycolysis Pyruvate, lactate, ATP Pyruvate + ATP → directly used by muscle cell LACTATE → some enters blood → liver → converted to GLUCOSE → bloodThus, muscle cells contribute to blood glucose...INDIRECTLY by way of liver processing lactateDefine glycogenolysis- Hydrolysis of glycogen - To glucose-6-phosphate monomers - In liver and skeletal muscleLIPIDS.Lipids are broken down via..LipolysisDefine lipolysis• Hydrolysis of triglycerides to glycerol and fatty acids • In adipose tissue • Glycerol and fatty acids diffuse into blood → liver • Glycerol can be ENZYMATICALLY converted to GLUCOSE through series of steps in liverPROTEIN/After ... of being in the post-absorptive state, protein must also become a source of glucosefew hoursIs this not dangerous?• Large amounts muscle and tissues can be catabolised • without significant cellular malfunction (so initially ok)Protein loss in short fast = ok Continued protein loss in prolonged fast = dangerous Why?Disrupts cell function ↓ Sickness ↓ eventually DEATHFate of protein in gluconeogenesis• Protein broken down → amino acids → blood → liver • Amino acids converted via the α-KETO ACID pathway → glucose (transamination to pyruvate?) • Glucose → bloodDefine gluconeogenesis• Synthesis of new glucose molecules • From non-carbohydrate precursors (amino acids, glycerol)FOR 1 MOLECULE OF GLUCOSE FORMED ... MOLECULES OF ATP OF CONSUMED1 GLUCSE FORMED : 6 ATP CONSUMEDFAT METABOLISM.Location of body fat stores• Most in adipocytes, form adipose tissue • Some in hepatocytesDietary lipids consists of 5 lipid forms:• Triglycerides (95%) (TAGs/TGs) • cholesterol • Phospholipids • FFAs (free fatty acids) • Fat-soluble vitamines (A,K,E,D)Body's energy store is accounted for by - TAGs = ..% - Protein = ..% - Carbohydrates = ..%- TAGs = 78% - Protein = 21% - Carbohydrates = 1%78% of energy stored in the body is stored in the form of triglycerides.Define lipids• ESTERS of fatty acids and certain alcohol compounds (many different types - fats/oils/waxes/steroids/hormones/phospholipids/cholesterol - fats only one type of lipid! All hydrophobic, non-polar and mostly made up of hydrocarbon chains)Lipid functions:• Energy store • Structural component of cell membranes • Steroid hormones (also insulation, organ protection, solubilise fat-soluble vitaminsLipids are hydrophobic. How then are they transported in water of the blood or ecf?LIPOPROTEINSWhat are lipoproteins?• Means of transporting hydrophobic lipids in the blood (/ecf) • Consist of single outer layer of phospholipids and cholesterol (hydrophilic ends facing outward) • Hydrophobic/lipophilic ends point towards core of lipids (apoproteins embedded in membrane to stabilise structure + determine its fate)Lipoprotein 4 examples + site of synthesis:1. HDL - liver 2. LDL - plasma 3. VLDL - liver 4. Chylomicrons - intestinal cellsHDL and LDL both carry ... The main carrier being...cholesterol LDLsHDL - good/bad - function• HDL = 'good cholesterol' • formed in liver • REMOVE EXCESS cholesterol from blood & tissue to liver • Liver secretes it in bile/converts it to bile saltsLDL - good/bad - function (remember they are still required for normal metabolism and life! But excess is bad)• LDL = 'bad cholesterol' • formed in plasma • main cholesterol carrier • DELIVER cholesterol to cells throughout the body • LDL has protein component on surface that binds to receptors on the cell plasma membrane of cell → ENDOCYTOSIS of LDL into cellWhy LDL is considered "bad"• Delivers cholesterol to cells • High plasma concentrations of LDL ↓ Associated with INCREASED DEPOSITION of cholesterol in ARTERIAL WALLS ↓ Increased incidence of heart attackLDL is still ESSENTIAL to cells however:• Supplies them with cholesterol required for • Cell membrane synthesis • Steroid hormone synthesis in adrenal glands and gonads - aldosterone - cortisol - testosterone & oestrogenVLDL - Synthesised where - Function• Liver hepatocytes • Transport (endogenous) triglycerides (from glucose in liver) from liver → adipocytesChylomicrons - Synthesised where - Function• Enterocytes (endoplasmic reticulum) • Transport dietary lipids (exogenous) from GI tract → various tissues of the body such as adipose/caridac/skeletalFATTY ACID CATABOLISM.Under resting conditions, around ... of the energy used by ....... comes from the CATABOLISM OF FA.Half Muscles, liver, kidneysWhere is fat stored in body?• Most cells do store some degree of fat • Hepatocytes • But most is stored in ADIPOCYTES as SINGLE FAT DROPLET - almost fills the cytoplasm • Clusters of adipocytes form ADIPOSE tissue • Adipose tissue = underlying the skin / surrounding internal organsAdipocyte function (absorptive + post-absorptive)• Absorptive: synthesise and store TAGs • Post-absorptive: breakdown TAGs → release glycerol and fatty acids into blood → transported by albumin → taken up by cells → used in metabolism to provide energy for ATP productionAdipocytes fat stores broken down. Glycerol and fatty acids released into blood and taken up by cells. Cells produce ATP from the fatty acids. Involves ... of fatty acid followed by ... This occurs in the ... of the cell• Fatty acid activation • Beta-oxidation • MitochondriaDescribe the processFA ACTIVATION: 1. acetyl-CoA molecule attaches to end of FA at carboxyl group 2. ATP broken down → AMP + 2Pi 3. produces CoA derivative of the fatty acid BETA -OXIDATION 4. the coenzyme A derivative of the fatty acid proceeds through β-oxidation 5. each cycle cleaves off 2C from the FA → acetyl-CoA and 2 pairs of H (one pair to FAD and one pair to NAD⁺)...process continued - fate of H on coenzymes - fate of acetyl CoA cleaved off - fate of remaining fatty acid (acyl-CoA)6. hydrogen atoms from the coenzymes are used in OXIDATIVE PHOSPHORYLATION to produce ATP 7. acetyl-CoA molecule used in KREB'S CYCLE 8. remaining acyl-CoA used again in cycle (but now 2C shorter)β-oxidation• Fatty acid catabolised to produce acetyl-CoA for use in TCA cycle • Acyl-CoA enters β-oxidation (fatty acid CoA derivative) • 2 x 2H cleaved off FAD → FADH₂ NAD⁺ → NADH + H⁺ • 2C cleaved off → acetyl CoAEach passage through the β-oxidation sequence ...SHORTENS the fatty acid chain by TWO CARBONS until all the carbon atoms have been transferred to molecules of acetyl-CoAMolecules produced in β-oxidation ... lead to the production of ... via ..• Acetyl-CoA, FADH₂ and NADH • production of CO₂ and ATP • via Kreb's and oxidative phosphorylation