Liver Physiology Flashcards

Question

Female daily requirement of vitamin A

Answer 1

0.7 mg/day

Answer 2

Vision Reproduction Growth Stabilisation of cellular membranes

Answer 3

Used to form rhodopsin in the rod cells of the retina

Answer 4

Spermatogenesis in male Prevention of fetal resorption of female

Answer 5

Rare in affluent countries as vitamin A levels drop only when liver stores are severely depleted. Deficiency may occur due to fat malabsorption Clinical Features: -Night blindness -Xeropthalmia -Blindness

Answer 6

Night blindness Xerophthalmia- inability to produce tears Blindness

Answer 7

Ferritin Vitamins Clotting factors

Answer 8

Abdominal pain, nausea and vomiting Severe headaches, dizziness, sluggishness and irritability Desquamation of the skin

Answer 9

Joint and bone pain Hair loss, dryness of the lips Anorexia Weight loss and hepatomegaly

Answer 10

Water soluble vitamins pass more readily through the body so require more regular intake than fat soluble vitamins Fat soluble vitamins more readily stored

Answer 11

Reversible yellowing of the skin Does not cause toxicity

Answer 12

Increased intestinal absorption of calcium Resorption and formation of bone Reduced renal excretion of calcium

Answer 13

Sunlight Vitamin D3 = fish, meat Vitamin D2= supplements

Answer 14

Demineralisation of bone: - rickets in children - osteomalacia in adults

Answer 15

Non-adipose cells such as liver and plasma - labile and fixed pool Adipose cells- fixed pool

Answer 16

Important antioxidant

Answer 17

Nuts Oils Avocado Carrots Spinach

Answer 18

Fat malabsorption eg cystic fibrosis Premature infants Rare congenital defects in fat metabolism eg abetalipoproteinaemia

Answer 19

Cholecalciferol

Answer 20

25-hydroxyvitamin D3

Answer 21

1,25-dihydroxyvitamin D3

Answer 22

Haemolytic anaemia Myopathy Retinopathy Ataxia Neuropathy

Answer 23

Relatively safe

Answer 24

Adipose cells

Answer 25

Non-adipose cells such as liver and plasma

Answer 26

K1 K2 K3 K4

Answer 27

Phylloquinone Synthesised by plants and present in food

Answer 28

Menaquinone Synthesised in humans by intestinal bacteria

Answer 29

Menadione Synthetic

Answer 30

Menadiol Synthetic

Answer 31

Rapidly taken up by the liver Transferred to very low density lipoproteins (VLDL) and low density lipoproteins (LDL) which carry it into the plasma

Answer 32

Activation of some blood clotting factors Necessary for liver synthesis of plasma clotting factors II, VII, IX , X

Answer 33

Prothrombin time

Answer 34

Green leafy vegetables Sunflower pil

Answer 35

Haemorrhagic disease of the newborn: vitamin K injection given to newborn babies Rare in adults unless on warfarin

Answer 36

K1 is relatively safe Synthetic forms are more toxic Can result in oxidative damage, red cell fragility and formation of methaemoglobin.

Answer 37

Collagen synthesis Antioxidant Iron absorption

Answer 38

Fresh fruit Vegetables

Answer 39

Scurvy: Easy bruising and bleeding Teeth and gum disease Hair loss

Answer 40

Treated with vitamin C Improves symptoms quickly Joint pain gone within 48 hours Full recovery within 2 weeks

Answer 41

Doses > 1g/day can cause GI side effects No evidence that increased vitamin C reduces the incidence or duration of colds.

Answer 42

Cobalamins

Answer 43

Methylcobalamin 5-deoxyadenosylcobalamin

Answer 44

Food by acid and enzymes in stomach

Answer 45

Binds to R protein to protect it from stomach acid Released from R proteins by pancreatic polypeptide Intrinsic factor produced by the stomach needed for absorption IF-B12 complex absorbed in terminal ileum

Answer 46

Intrinsic factor

Answer 47

Terminal ileum

Answer 48

Meat Fish Eggs Milk

Answer 49

Pancreatic polypeptide

Answer 50

Pernicious anaemia – autoimmune destruction of IF-producing cells in stomach. Malabsorption – lack of stomach acid, pancreatic disease, small bowel disease. Veganism

Answer 51

Macrocytic anaemia Peripheral neuropathy in prolonged deficiency

Answer 52

found in may foods fortified with folic acid. Individuals have higher requirements in pregnancy.

Answer 53

Coenzyme in methylation reactions DNA synthesis Synthesis of methionine from homocysteine

Answer 54

Malabsorption Drugs that interfere with folic acid metabolism (anticonvulsants, methotrexate) Disease states that increase cell turnover (e.g. leukaemia, haemolytic anaemia, psoriasis)

Answer 55

High homocysteine levels Macrocytic anaemia Foetal development abnormalities (neural tube defects)

Answer 56

Intrinsic pathway activated by contact Extrinsic pathway activated by FVII coming in contact with tissue factor Initiates a cascade which ultimately results in fibrin clot formation

Answer 57

FVII coming in contact with tissue factor

Answer 58

I (fibrinogen) II (prothrombin) IV V VI VII

Answer 59

Prothrombin time (extrinsic pathway) International normalised ratio Activated partial thromboplastin time (aPTT) (intrinsic pathway)

Answer 60

Prothrombin time

Answer 61

Activated partial thromboplastin time

Answer 62

May indicate a deficiency in the synthetic capacity of the liver

Answer 63

Liver disease DIC severe GI bleeding Some drugs Vitamin K deficiency

Answer 64

Xenobiotics

Answer 65

Functionalisation - non synthetic Add or expose functional groups -OH, -SH, -NH2, -COOH

Answer 66

Conjugation- biosynthetic Conjugation with endogenous molecules: glucuronic acid, sulphate, glutathione Covalent bonds formed

Answer 67

Make compounds non-toxic and water soluble

Answer 68

foreign substances that don’t have nutritional value. Xenobiotic compounds are mostly in the diet, but we also breathe in potential toxins, and importantly the body treats medications as xenobiotics.

Answer 69

Small increase

Answer 70

Large increase

Answer 71

Polar and hydrophilic Eg paracetamol

Answer 72

has a number of hydroxyl groups which make the molecule polar and facilitate excretion in the urine.

Answer 73

Most in liver some takes place in the lungs & small intestine before compounds are absorbed into the bloodstream.

Answer 74

* inactivation and facilitated elimination of drugs and other xenobiotics * active metabolites formed, with similar or occasionally enhanced activity * activation of pro-drugs * toxification of less toxic xenobiotics

Answer 75

Smooth endoplasmic reticulum

Answer 76

Encoded by a superfamily of more than 50 different genes in humans

Answer 77

All present in sER- microsomal enzymes All oxidise the substrate and reduce oxygen All have a cytochrome reductase subunit which uses NADPH Are inducible- enzyme activity may be increased by certain drugs, some dietary components and some environmental toxins eg smoking Generate a reactive free radical compound

Answer 78

Certain drugs, some dietary components, some environmental toxins eg smoking

Answer 79

Hydroxylation (addition of -OH groups) N- and O- dealkylation (removal of -CH side chains) Deamination (removal of -NH side chain) Epoxidation (formation of epoxides)

Answer 80

Hydrogen addition (unsaturated—>saturated) Donor molecules include GSH, FAD, NAD(P)H

Answer 81

Splitting of C-N-C (amide) and C-O-C (ester) bonds

Answer 82

To be filtered and excreted in the urine a molecule needs to be polar (thus more hydrophilic) increasing its solubility Can occur via 2 methods

Answer 83

Glycoside conjugation - glucuronidation (most common) Sulphate - sulphation Glutathione (GSH)

Answer 84

A = absorption D - distribution M = metabolism E = elimination/excretion

Answer 85

Damage proteins, lipids and can bind to DNA (carcinogens)

Answer 86

React with O2 and release free radicals

Answer 87

Tend to be lipophilic, non-polar and non-ionised at physiological pH to allow pharmaceutical action

Answer 88

Smooth ER of liver, kidneys and intestinal mucosa

Answer 89

Mono-oxygenases (CYPs, FMOs)

Answer 90

Majority of drug biotransformation

Answer 91

Yes by diet and drugs

Answer 92

Cytoplasm and mitochondria of hepatocytes

Answer 93

Protein oxidases, esterases etc

Answer 94

Non-specific enzymes for conjugation

Answer 95

No but have polymorphisms

Answer 96

Phase I biotransformation

Answer 97

CYP3A4 Responsible for 2/3 all known drugs

Answer 98

At least 10

Answer 99

Molecule binds to an intracellular receptor within the cytoplasm This molecule-receptor complex migrates to the nucleus Increases transcription of mRNA for cytochrome-P450s Increases the effect of the CYP One substance can induce a number of enzymes

Answer 100

Contain a haem component which is capable of oxidising molecules (-OH addition) by becoming reduced themselves The reductase use NADPH to become active It reduces CYPs allowing the oxidation of the foreign molecule Reaction forms water and has an intermediate of a haem free radical Overall the addition of the -OH group increases the solubility of the molecule

Answer 101

Complete inactivation and elimination Formation of another active compound Activation of pro-drugs Toxification of less toxic Xenobiotics Active drug to reactive intermediates

Answer 102

Removal of drugs/ metabolites by transporter-mediated elimination via the liver gut kidney and lung

Answer 103

Liver Gut Kidney Lung

Answer 104

Eg phenobarbital (barbiturate derivative) Metabolised using phase I and II distributed into fat and bound to plasma proteins so metabolism is slow

Answer 105

Can have similar or new activity Eg codeine breaking down into morphine Eg diazepam into oxazepam

Answer 106

Eg hetacillin converted into ampicillin Eg into-glycerine into nitric oxide

Answer 107

Eg benzopyrene in cigarette smoke Bind to DNA and induce CYPs which increase epoxide levels

Answer 108

CYP1A2 can be induced by smoking This increased activity has effects on metabolism of other molecules Eg clozapine- dose has to be tightly controlled depending on how much the patient smokes

Answer 109

Grapefruit juice has effects on medications eg statins Contains products that inhibit CYPs Statins become more potent Grapefruit is contraindicated

Answer 110

Usually disposed of safely by glucuronidation (50%) as glucuronide has a lot of -OH groups, also by sulfation (40%) Harmful intermediate NAPQI is created from CYP2E1 (10%) If normal pathways are overwhelmed, CYP2E1 becomes more significant and more NAPQI created- normally metabolised by glutathione-S-transferase but this is overwhelmed by high levels Hepatocytes then become damaged

Answer 111

Uses the same enzyme as paracetamol so has a dual effect when taken together Enzymes are induced by 2 factors More likely to go done the harmful route- enzymes overwhelmed

Answer 112

Acetylcysteine

Answer 113

Glucuronidation Sulfation

Answer 114

GSH-depletion

Answer 115

Alcohol is polar but also slightly lipid soluble Can be excreted (2-10%) but is more commonly used as fuel Metabolised in acetaldehyde (tocis) Further metabolism to acetate by ALDH which can be used in Kreb’s cycle This second metabolism becomes overwhelmed and acetaldehyde builds up

Answer 116

Acetaldehyde

Answer 117

Microsomal ethanol oxidising system (MEOS) also produces acetaldehyde Chronic alcohol use increases CYP2E1 levels 5-10 fold therefore alcohol is metabolised quicker Acetaldehyde is produced quicker and in larger quantities- more toxic Results in liver damage from the production of free radicals

Answer 118

Microsomal ethanol oxidising system Alcohol dehydrogenase

Answer 119

can result in increased blood concentrations of certain medications (less breakdown).

Answer 120

phenobarbital

Answer 121

Cholecalciferol

Answer 122

Ergocalcaiferol

Answer 123

Liver is important in metabolic activation of vitamin D

Answer 124

pre-hepatic, hepatic or post-hepatic

Answer 125

caused by increased haemolysis- results in increased presence of unconjugated bilirubin in the blood as the liver is unable to conjugate it all at the same rate • Any bilirubin that manages to become conjugated will be excreted normally, yet it is the unconjugated bilirubin that remains in the blood stream to cause the jaundice.

Answer 126

• Tropical disease eg malaria, yellow fever • Genetic disorders eg sickle-cell anaemia, Gilbert’s syndrome • Haemolytic anaemias

Answer 127

caused by liver impairment- causes the decreased ability of the liver to conjugate bilirubin, resulting in the presence of conjugated and unconjugated bilirubin in the blood • The liver loses the ability to conjugate bilirubin, but in cases where it also may become cirrhotic, it compresses the intra-hepatic portions of the biliary tree to cause a degree of obstruction. This leads to both unconjugated and conjugated bilirubin in the blood

Answer 128

• Viral hepatitis • Hepatotoxic drugs eg paracetamol overdose, alcohol abuse

Answer 129

caused by the blockage of bile ducts- results in back-flow of conjugated bilirubin into the blood as it cannot move past the obstruction • bilirubin that is not excreted will have been conjugated by the liver, hence the result is a conjugated hyperbilirubinaemia.

Answer 130

Gallstones • Hepatic tumours • Pancreatic tumours

Answer 131

• inherited disorder where there is hyperbilirubinaemia (excess bilirubin in bloodstream) due to a fault in the UGT1A1 gene leading to a deficiency in UPD-gluconoryltransferase. • Results in slower conjugation of bilirubin in the liver so it builds up in the bloodstream • When well, patients are usually asymptomatic and have normal bilirubin levels • Under physiological stressors such as illness, alcohol abuse and extreme exercise, patients can become markedly jaundiced

Answer 132

excessive conjugated bilirubin excreted through the kidneys

Answer 133

reduced levels of stercobilin entering the GI tract. Obstructive or post-hepatic liver cause as normal faeces get their colour from bile pigments

Answer 134

Between adjacent hepatocytes, grooves in the cell membranes provide room for bile canaliculi: these are small ducts that accumulate the bile produced by hepatocytes. Bile flows first into bile ductules and then into bile ducts which unite to form the larger left and right hepatic ducts. These merge and exit the liver as the common hepatic duct. The common hepatic duct then joins with the cystic duct (from the gallbladder), forming the common bile duct which flows into the duodenum.

Answer 135

yellow bile pigment produced through the breakdown of red blood cells (haemolysis). It is metabolised prior to excretion through the faeces and urine. Bilirubin exists in 2 forms: conjugated and unconjugated. Unconjugated bilirubin is insoluble in water so can only travel in the bloodstream if bound to albumin and cannot be directly excreted from the body. Whereas, conjugated bilirubin is water soluble so it can travel in the bloodstream and excreted out of the body.

Answer 136

Conjugated and unconjugated

Answer 137

insoluble in water so can only travel in the bloodstream if bound to albumin and cannot be directly excreted from the body

Answer 138

water soluble so it can travel in the bloodstream and excreted out of the body.

Answer 139

reticuloendothelial cells are macrophages which are responsible for the maintenance of blood through destruction of old or abnormal cells. They take up red blood cells and metabolise the haemoglobin present into its individual components: haem and globin. Globin is further broken down into amino acids which are recycled. Haem is broken down into iron and biliverdin, catalysed by haem oxygenase. The iron is recycled and the biliverdin is reduced to form unconjugated bilirubin.

Answer 140

In the bloodstream, unconjugated bilirubin binds to albumin to facilitate its transport to the liver. In the liver, glucuronic acid is added to unconjugated bilirubin by the enzyme glucuronyl transferase. This forms conjugated bilirubin, which is soluble, allowing it to be excreted into the duodenum in bile.

Answer 141

Once in the colon, colonic bacteria deconjugate bilirubin and convert it into urobilinogen. Around 80% is further oxidised by intestinal bacteria and converted to stercobilin and then excreted through faeces (giving it its colour). Around 20% of the urobilinogen is reabsorbed into the bloodstream as part of enterohepatic circulation. It is carried to the liver where some is recycled for bile production, and a small percentage reaches the kidneys. In the kidneys, it is further oxidised to urobilin and then excreted into the urine.

Answer 142

reticuloendothelial cells

Answer 143

Haem and globin

Answer 144

Amino acids which are recycled

Answer 145

Iron and biliverdin

Answer 146

Haem oxygenase

Answer 147

It is recyled

Answer 148

It is reduced to form unconjugated bilirubin

Answer 149

glucuronyl transferase

Answer 150

Glucuronic acid

Answer 151

In the bile into the duodenum

Answer 152

Colonic bacteria deconjugates it forming urobilinogen

Answer 153

Urobilinogen

Answer 154

further oxidised by intestinal bacteria and converted to stercobilin and then excreted through faeces (giving it its colour)

Answer 155

Stercobilin

Answer 156

reabsorbed into the bloodstream as part of enterohepatic circulation. It is carried to the liver where some is recycled for bile production, and a small percentage reaches the kidneys. In the kidneys, it is further oxidised to urobilin and then excreted into the urine.

Answer 157

Stercobilin

Answer 158

Heart —> abdominal aorta —> hepatic artery proper —> liver —> hepatic veins —> inferior vena cava —> heart

Answer 159

Organised in lobules with a central hepatic wein Hexagon- portal triads in the corners

Answer 160

Approximately 500

Answer 161

Detoxification - filters and cleans blood of waste products (drugs, hormones) Immune functions - fights infections and diseases (RE system) Involved in synthesis of clotting factors, proteins, enzymes, glycogen and fats Production of bile and breakdown of bilirubin Energy storage- glycogen and fats Regulation of fat metabolism Ability to regenerate

Answer 162

Maintains a continuous supply of energy for the body by controlling the metabolism of CHO and fats

Answer 163

Endocrine glands eg pancreas, adrenal, thyroid Nerves

Answer 164

Esters of fatty acids and glycerol or other compounds (cholesterol) Large and diverse group of naturally occurring organic compounds that are insoluble in water Variety of structure and functions

Answer 165

1 glycerol molecule esterified to 3 fatty acids bonded at carboxylate head

Answer 166

Storage form of fat in our body -adipocytes -hepatocytes -elsewhere

Answer 167

Lining up close together Esters are solid at room temperature Solid ‘fats’

Answer 168

Needs more space due to kink in chain Less tightly packed MUFA, PUFA Esters are liquid at room temperature ‘Oils’

Answer 169

Energy reserve Structural and other functions Hormone metabolism

Answer 170

Part of cell membranes Integral to form and functions of cells Inflammatory cascade (LC-PUFAs precursors to eicosanoids, eg prostaglandins)

Answer 171

LC-PUFAs precursors to eicosanoids e.g. prostaglandins

Answer 172

Cholesterol is backbone of adrenocorticoid and sex hormones Vitamin D

Answer 173

30-40 days

Answer 174

Often transported as TGs or FAs bound to albumin or within lipoproteins Triglycerides cannot diffuse through cell membrane Fatty acids are released through lipases to facilitate transport into cells- in the cell re-esterified to triglycerides

Answer 175

Diffusion through the lipid bilayer of the cell membrane Facilitated transport

Answer 176

Increases if increased substrate or increase in receptor molecules Several transporter systems

Answer 177

FA binding protein = mitochondrial AST - induction to increased expression may result in increased uptake of fatty acid in hepatocytes FAT -fatty acid translocase FATP- fatty acid transport polypeptide

Answer 178

Hardly kinked Hard to metabolise

Answer 179

polar derivates of of cholesterol - aid diestestion of fats and fat soluble vitamins Ba are amphipathic and emulsify fat globules into smaller miclelles -= hence higher surface area for lipid hydrolysing emzymes – they act as detergents (washing up liquid)

Answer 180

Secretion of BA and cholesterol through bile is the only excretion mechansim of cholesterol

Answer 181

Reabsorption of bile acids and cholesterol in the ileum

Answer 182

Resins- like cholestyramine Diet- oat, bran fibre and fruit pectins

Answer 183

From the gut are transported through the lymphatic system to be delivered to muscle and adipose tissue, bypassing the liver- protects the liver from a large fatty acid influx

Answer 184

Excess intake - triglycerides in Chylomicrons remnants reach liver Increased de novo synthesis Increased fatty acid influx from lipolysis in adipocytes Reduced export Reduced oxidation in liver

Answer 185

Fat storage in adipocytes Stimulates LPL (lipoprotein lipase)—> breakdown of triglycerides, releases free fatty acids to store )in form of TG) in adipocytes Reduced activity of hormone sensitive lipase (HSL) leading to reduced fatty acid export from adipocytes

Answer 186

Increased lipolysis in adipocytes leading to increased triglyceride in circulation Increased ‘offer’ of fatty acids to hepatocytes leading to increased uptake Increased glucose level leads to less demand for lipids to be used as energy source

Answer 187

Lipoprotein lipase —> free fatty acids —> facilitated diffusion into adipocytes—> triglycerides—> hormone sensitive lipase —> free fatty acid -> hepatic lipase —> facilitated diffusion into hepatocytes

Answer 188

Lipoprotein lipase Hormone sensitive lipase Hepatic lipase

Answer 189

Insulin concentration and sensitivity

Answer 190

Export in lipoproteins as energy source and structural components for membranes

Answer 191

Sequential extension of alkanoic chain staring from Acetyl-CoA via serial decarboxylative condensation reactions

Answer 192

Nutrition and hormones High KH diet increases hepatic lipogenesis- KH are burnt to generate ATP, surplus glucose fills glycogen stored and further surplus is converted to fatty acids Fasting and fat feeding inhibit it

Answer 193

Long term energy storage

Answer 194

Activated fatty acid synthase

Answer 195

Carbohydrate response element binding protein

Answer 196

0.75g/kg/day

Answer 197

Faecal loss- 10g/day Renal excretion- 70g/day in form of urea Skin/hair/sweat loss

Answer 198

Pregnancy Lactation Bodybuilder and anabolic steroids Recovery ohase

Answer 199

Protein malnutrition Severe illness/sepsis/trauma/burns Corticosteroids Cahexia: malignancy/heart failure/uraemia Essential amino acid deficiency

Answer 200

concept that compares the amount of nitrogen (overwhelmingly in the form of dietary proteins) that enters the body compared to that which is excreted from the body. Nitrogen is said to be in balance when the two are roughly equal (+/- 4g/day)

Answer 201

Intake of nitrogen greater than excretion Anabolic- gain of protein

Answer 202

Excretion is greater than intake Catanolism- loss of protein

Answer 203

they can be incorporated ‘as is’ with other amino acids to form peptides and proteins they can be modified to form other biomolecules such as nucleotide bases and neurotransmitters they can have their nitrogenous amino group removed (to be excreted as urea) and have their ‘carbon backbone’ reutilised for energy, either via the Citric acid cycle or through the formation of glucose via gluconeogenesis. No amino acid is stored.

Answer 204

Adequate calories but inadequate proteins Protein-energy metabolism Features: oedema , fatty liver, dermatoses

Answer 205

Both protein and calories insufficient

Answer 206

Amino acids are absorbed from the gut and enter the portal circulation where they travel to the liver, which is the centre for the majority of metabolic processes. Accordingly, it is also the site where most of the humoral, that is to say, blood-bourne proteins are formed. They may be utilised here in protein formation, or be used to form other nitrogen-containing compounds. Some enter the systemic circulation to supply the builiding blocks of protein to different bodily tissues. Those which cannot be used in such a fashion have their amino groups removed and their carbon backbones used as metabolic substrates, helping to form carbohydrates like glucose from gluconeogenesis or fatty acids to form triacylglycerols.

Answer 207

Dietary protein —> denatured protein —> oligopeptides and AAS —> amino acids in blood stream (active transport)

Answer 208

HCl and pepsin in stomach

Answer 209

Chymotrypsin Trypsin Aminopeptidase In small intestine

Answer 210

Enterocyte peptidases In enterocytes

Answer 211

first stage is via a cell surface channel where it is cotransported with a sodium ion. Then via the basal membrane is is actively transported into the portal veinous circulation by an ATP consuming process. From there it travels into the liver.

Answer 212

Carbon backbone produces gluconeogenic/TCA cycle intermediates

Answer 213

Carbon backbone produces Acetyl-CoA/ Acetoacetyl-CoA

Answer 214

Leucine Lysine

Answer 215

Phenylalanine Valine Leucine Isoleucine Tryptophan Methionine Threonine Histidine

Answer 216

Cannot be synthesised de novo in vivo

Answer 217

Albumin Coagulation factors IGF-1 C-reactive protein Carrier proteins eg caeruloplasmin Apolipoproteins

Answer 218

Maintains oncotic blood pressure Important carrier protein eg for sex hormones, magnesium, calcium and drugs

Answer 219

Heme Creatinine Purine bases

Answer 220

Can produce non-peptide molecules eg neurotransmitters, nitric oxide and nucleotides

Answer 221

Purine and pyrimidine bases

Answer 222

Nitric oxide

Answer 223

Serotonin Melotonin

Answer 224

Dopamine Catecholamines (enable fight or flight response) Thyroid hormones Melanin

Answer 225

Carbon backbone after R group of amino acid cleaved Used in kreb’s cycle eg alanine —>pyruvate

Answer 226

Aminotransferase (with PLP group)

Answer 227

Alanine + Alpha-ketoglutatate <—> pyruvate + glutamate Alanine aminotransferase (ALT)

Answer 228

In most transamination reactions, a-ketoglutarate and glutamate form one of the a-ketoacid/amino acid pairs. This means a-ketoglutarate is a receiver of nitrogen (the amino group), which is transferred to glutamate.

Answer 229

Forms ammonia (NH4+) which is combined with bicarbonate to form carbamyl phosphate Enters urea cycle to produce urea which is excreted

Answer 230

Glutamate dehydrogenase

Answer 231

NADP + H20 ——> NADPH + NH4+ (ammonium)

Answer 232

Ammonium and bicarbonate

Answer 233

Faulty/aging/obsolete proteins Signal transduction Flexible system to meet protein/energy requirements of environment

Answer 234

Proteasome (ubiquitin-dependent) Lysosome

Answer 235

Mark of death Small protein Carboxyl group forms isopeptide bond with multiple lysine residues Formation of ubiquitin chains (stronger signal, especially >4)

Answer 236

Ubiquitin-activating enzyme Ubiquitin-conjugating enzyme Ubiquitin-protein ligase

Answer 237

The executioner

Answer 238

N-terminal residues determine protein half-life PEST sequences (proline, glutamate, serine, threonine) Cyclin destruction box

Answer 239

Proteolytic enzymes within lysosome separated from cytosolic components

Answer 240

Macroautography Microautography Chaperone-mediated autographs Endocytosis/phagocytosis

Answer 241

Non-selective ER derived autophagisomes engulf cytosolic proteins/aggregates organelles Lysosome fuses with this to initiate proteolysis

Answer 242

Non-selective Invaginations of lysosomal membrane engulf proteins/organelles

Answer 243

Selective Chaperone protein hsc70 in cytosolic and intralysomal accompany specific cytosolic proteins in response to stressors (fasting/oxidative stress etc)

Answer 244

Extracellular substances

Answer 245

Autosomal recessive condition 1 in 200000 Defect in transporter leads to cystine accumulation in tissue lysosomes Eye and kidney problems

Answer 246

Proteolysis Gluconeogenesis

Answer 247

Protein synthesis

Answer 248

Glucose-alanine cycle transports nitrogen from amino acid breakdown from the tissues to the liver, whilst recycling a carbon backbone that can be converted to glucose for energy

Answer 249

Formed from BCAA degradation in the tissues In the fasting state, it is an important metabolic fuel for the kidney and gut and provides ammonia to buffer proton diuretics in metabolic acidosis states

Answer 250

Isoleucine/valine/leucine Major amino acids that can be oxidised in tissues other than the liver, especially skeletal muscle

Answer 251

Stimulates: Glycogenolysis Gluconeogenesis Amino acid degradation Ureagenesis Entry of amino acids to liver

Answer 252

Through bile Enterohepatic circulation

Answer 253

Acyl-CoA or by lecithin by cholesterol acyltransferase

Answer 254

Cholesterol acyltransferase

Answer 255

A core containing triglycerides and cholesterol-esters A surface monolayer of phospholipids cholesterol and specific proteins (eg apoproteins)

Answer 256

Protein to lipid ratio

Answer 257

Chylomicrons VLDL LDL HDL

Answer 258

Largest lowest density High lipid to protein ratio Highest triglyceride content

Answer 259

Very low density lipoprotein 2nd highest in triglycerides as percentage of weight

Answer 260

Low density lipoprotein High cholesterol ester as percentage of weight Raised by saturated fats and trans fatty acids

Answer 261

High density lipoprotein Low lipid to protein ratio

Answer 262

Taken up by the liver via receptor-mediated Endocytosis Recognition of ApoE by hepatocyte surface receptors

Answer 263

Microsomal TAG transfer protein adds the lipid components to ApoB Transported in vesicle to Golgi apparatus where ApoB is glycosylates This buds off the Golgi and migrate the sinusoidal membrane of the hepatocytes Vesicle fuse with the membranes and VLDL is released

Answer 264

VLDL production

Answer 265

Microsomal TAG transfer protein

Answer 266

Golgi apparatus

Answer 267

Acetyl-CoA —> Malonyl-CoA Catalysed by Acetyl-CoA carboxylase Rate is also related to FAS-FA synthetase

Answer 268

Acetyl-CoA carboxylase

Answer 269

Reduced in fasting Hepatic glycogen stores depleted Triglycerides broken down in adipocytes and more free fatty acids released Oxidised in the liver as an energy source

Answer 270

Portal vein Hepatic artery Lymphatics

Answer 271

Triglycerides Lipoproteins Chylomicron remnants HDL (Often transported as triglycerides of fatty acids bound to albumin or within lipoproteins)

Answer 272

Hormone sensitive lipase release free fatty acids Hepatic lipase enables the uptake into hepatocytes

Answer 273

Release controlled by hormones Released as VLDLs, energy substrates and detoxified substrates Storage capacity of far higher than demand

Answer 274

Chylomicrons can bypass the liver as transported by lymphatic system Protects liver from large fatty acid influx

Answer 275

Peroxysomal beta-oxidation Mitochondrial beta-oxidation ER Microsomal Ω -oxidation (CYP4a catalysed)

Answer 276

Fatty acid oxidation is proportional plasma levels of free fatty acids released from adipocytes Peripheral fatty acid mobilisation when increased glucagon and decreased insukin

Answer 277

Increased glucagon Decreased insulin

Answer 278

Insulin Substrate (citrate, isocitrate)

Answer 279

Catecholamines Glucagon

Answer 280

FA synthetase Negative feedback- high FAS in hepatocytes inhibit FAS Related to de novo lipogenesis in the liver

Answer 281

Primarily involved in oxidation of fatty acids of various chain length Multistep process Progressive shortening into acetyl -CoA subunits - condensed into ketone bodies providing oxidisable energy to cells - enter tricarboxyl acid cycle- resulting in H20 and CO2

Answer 282

CPT (carnitine palmitosyl transferase), carnitine concentration and malonyl-CoA (which inhibits CPT)

Answer 283

Genetic disorders inhibiting mitochondrial oxidation, certain drugs eg alcohol and toxins

Answer 284

Very toxic Inhibits mitochondrial fatty acid oxidation

Answer 285

4 step process is repeatedly performed to shorten chain length Each step can be carried out by at least 2 enzymes

Answer 286

Leads to micro-vesicular steatosis

Answer 287

detoxification of -very long chain fatty acids (>C 20) -2-methyl-branched FAs -Dicarbolic acids – very toxic – inhibiting mitochondrial fatty acid oxidation -Prostanoids -C-27 bile acid intermediaries

Answer 288

Normally a minor metabolic pathway but in fat overload increases CYP4A enzymes oxidise saturated and unsaturated fatty acids Ω-hydroxylation in the ER, followed by decarboxylation of the Ω-hydroxy fatty acid in the cytosol – in turn enter the β-oxidation pathway Dicarboxyl FA act as ligands to PPARά – induction of the oxidation systems

Answer 289

Lipid sensor- gene transcription Its activity determines whether fatty acids are stored as triglycerides in hepatocytes or oxidised for energy

Answer 290

Control activity of key transcription factors

Answer 291

Integration of signals from diverse pathways Co-ordination of the metabolic machinery for fatty acid metabolism

Answer 292

Peroxisome proliferator-activated receptors (PPAR ά, β and γ) Retinoid X receptor (RXR) Sterol regulator element binding protein (SREBP)

Answer 293

All PPARs (ά, γ,β/ δ) are involved in lipid homeostasis PPAR ά and β/ δ facilitate energy combustion PPAR γ facilitates energy storage PPAR ά is a lipid sensor – gene transcription Reduced PPAR ά sensing/activity leads to steatosis, possible by induction of CYP2E1, proinflammatory cytokines and TFN ά

Answer 294

Facilitate energy combustion

Answer 295

Facilitates energy storage

Answer 296

sensing/activity leads to steatosis, possible by induction of CYP2E1, proinflammatory cytokines and TFN ά

Answer 297

Increased energy storage

Answer 298

Increase plasma in fatty acids (mainly in TG) Excess dietary fat intake Excess dietary caloric intake overall But also increased flux of FAs Increased release of FAs from adipocytes Increased FA uptake in hepatocytes Decreased FA oxidation Decreased demand for lipids for fuel leading to increased storage Resulting in bland steatosis Insulin resistance augments the process

Answer 299

Overstorage of unmetabolised energy exceeding the energy combustion capability of the PPAR a mediated system

Answer 300

Fat content exceeding 5-10% of the weight of the liver

Answer 301

Increased steatosis (bland) Apoptosis of fat-laden hepatocyte releases TG and toxic FAs FAs induce CYP2E1 & FA oxidation systems →generation of reactive oxygen species (ROS) resulting in oxidative stress Oxidative stress induces release of proinflammatory cytokines from Kupffer cells (hepatitis) and ROS (and ethanol) activates stellate cells (fibrogenesis) Lipidperoxidation products develop immunogenic properties causing inflammation Gut derived products (e.g. endotoxins) also activate Kupffer cells

Answer 302

Adipose tissue inflammation Gut microbiota Oxidative stress Hepatocyte apoptosis Hepatic inflammation

Answer 303

1 simple fatty liver (steatosis) - a largely harmless build-up of fat in the liver cells that may only be diagnosed during tests carried out for another reason. Benign and no liver damage. Reversible 2 non-alcoholic steatohepatitis (NASH) - a more serious form of NAFLD, where the liver has become inflamed- estimated to affect up to 5% of the UK population 3 fibrosis - where persistent inflammation causes scar tissue around the liver and nearby blood vessels, but the liver is still able to function normally 4 cirrhosis - the most severe stage, occurring after years of inflammation, where the liver shrinks and becomes scarred and lumpy; this damage is permanent and can lead to liver failure and liver cancer

Answer 304

simple fatty liver (steatosis) - a largely harmless build-up of fat in the liver cells that may only be diagnosed during tests carried out for another reason. Benign and no liver damage Reversible

Answer 305

non-alcoholic steatohepatitis (NASH) - a more serious form of NAFLD, where the liver has become inflamed- estimated to affect up to 5% of the UK population

Answer 306

fibrosis - where persistent inflammation causes scar tissue around the liver and nearby blood vessels, but the liver is still able to function normally

Answer 307

cirrhosis - the most severe stage, occurring after years of inflammation, where the liver shrinks and becomes scarred and lumpy; this damage is permanent and can lead to liver failure and liver cancer

Answer 308

Diet and exercise ↓ Supply - Reduced intake of calories ↑ Demand – increased consumption The body will get energy from the “compartment” least in demand e.g. Exercise – fat burning Illness – muscle protein utilisation

Answer 309

High caloric load – energy load Metabolised in the liver – increased load leads to: Impairment and inhibition of PPARά and SREBP PPARά ↓ - ↓ fat oxidation SREBP ↓ - ↑ FAS - lipogenesis Damage to cell organelles – mitochondria, ER – reduced fat oxidation Apoptotic hepatocytes release TG and very-long chain FA – augment liver injury Stellate cell activation –leading to increased fibrogenesis

Answer 310

Under certain circumstances they may be needed to be consumed in the diet eg dependent on consumption of other amino acids

Answer 311

Arginine Cysteine Glycine Glutamine Proline Tyrosine

Answer 312

Alpha-ketoglutarate

Answer 313

Turning an amino acid into an intermediate in the TCA cycle Catalysed an amino transferase eg pyridoxal phosphate (PLP) dervived from vitamin B6 Taking an amine group from an amino acid to an alpha-ketoacid Turns it into an amino acid and becomes and alpha-ketoacid itself

Answer 314

Vitamin B6

Answer 315

Glutamate is converted back to alpha-ketoglutamate by glutamate dehydrogenase Produces ammonia Remove via the urea cycle

Answer 316

9-12 Can increase to 36

Answer 317

Rate of movement of albumin between vessels

Answer 318

Interstitium

Answer 319

Thoracic duct (lymphatics)

Answer 320

Binding and transport Maintenance of colloid osmotic pressure Free radicals Anticoagulant effects

Answer 321

Amino acid surplus to requirement for protein synthesis can be metabolised to non-nitrogenous substances Eg glucose , glycogen or fatty acids Can be oxidised to generate ATP

Answer 322

Alanine transported to hepatocytes in large quantities Alanine aminotransferase transaminates the amino group from glutamate- producing pyruvate Pyruvate substrate in TCA cycle to form glucose Glutamate recycled back and urea is formed Glucose taken up by muscle cells and used in glycolysis Pyruvate produced and lactate released as a by-product Pyruvate then converted back to alanine

Answer 323

Moves carbon atoms of pyruvate Moves excess ammonia from muscle to liver as alanine In liver, alanine yields pyruvate- starting block for gluconeogenesis Releases ammonia for conversion into urea] Energetic burden of gluconeogenesis imposed on liver rather than muscle (muscle ATP devoted to muscle contraction)

Answer 324

Aspartate Asparagine

Answer 325

Glutamate Glutamine Proline Arginine

Answer 326

Serine Cysteine Glycine

Answer 327

1. Glycogenesis 2. Pentose phosphate pathway 3. Formation of GA3P and DHAP to then form 2 pyruvate 4. Fatty acid synthesis

Answer 328

Forms ribose-5-phosphate from glucose Generates NADPH

Answer 329

Kreb’s cycle inhibited Citrate is broken down into oxaloacetate and acetyl-coa by citrate ligase Acety-CoA is converted to malonyl-CoA—-> fatty acids

Answer 330

Malonyl-CoA

Answer 331

Partly in the cytosol and partly in the mitochondria

Answer 332

Via up/down regulation of the enzymes responsible Long-term changes in level of dietary protein can result in 20-fold up regulation - could be seen in both high protein diets and starvation (protein breakdown)

Answer 333

1. Ammonia enters cycle by a Transamination reaction to form glutamate (recycle by deamination) 2. NH3 moves into the mitochondria and reacts with HCO3- (with ATP) to form carbamoyl phosphate catalysed by carbamoyl phosphate synthase 3. Carbmoyl phosphate reacts with ornithine to form citrulline catalysed by ornithine transcarbamylase 4. Moves out into cytoplasm through transporter 5. Reacts with aspartate and ATP to form arginine succinate catalysed by argininosuccinate synthase 6. This breaks down into arginine and releases demarcate catalysed by argininosuccinate lyase 7. Arginine reacts with water to produce ornithine releasing urea catalysed by arginase/ornithine aminotransferase 8. Ornithine then re-enters the mitochondria to continue the cycle

Answer 334

Albumin CRP Hormone binding globulins Apolipoproteins Other transport proteins eg caeruloplasmin, ferritin Factors in the complement cascade Inhibitors of clotting Fibrinolysis Inhibitors of fibrinolysis Complement

Answer 335

Immunoglobulins

Answer 336

Inflammation Liver disease Renal disease Burns/trauma Sepsis Malnutrition

Answer 337

Oedema Effusions Carrier proteins

Answer 338

Exudates vs Transudates Adjusting for electrolytes – esp Ca2+ Adjusting for hormone levels – eg free testosterone Renal disease

Answer 339

Reduced synthesis of clotting factors -Hepatic dysfunction -Vitamin K deficiency/malabsorption Reduced synthesis of inhibitors Production of abnormal/dysfunctional proteins Enhanced fibrolytic activity -Reduced clearance of activators of fibrinolysis -Reduced production of inhibitors Reduced hepatic clearance of clotting factors Disseminated intravascular coagulation -Multifactorial – includes endotoxaemia Platelet abnormalities -Number -Function Development of varices

Answer 340

Amino acid split into alpha-keto acid and NH4+

Answer 341

Low blood albumin

Answer 342

Avoidance of catabolism, glucose polymers when unwell Induction of anabolism – give dextrose 10% 2ml/kg/hr -> insulin! Low dietary protein, arginine, benzoate, phenylbutyrate Haemofiltration Liver transplantation, umbilical vein hepatocyte transfusion Gene therapy: NIH NGVL UPenn trial stopped after death (adenovirus E1 E4 del., fever, multi-organ failure)

Answer 343

Consumes 3 ATP molecules 4 high energy nucleotide PO4-

Answer 344

Production of the cycle intermediates

Answer 345

Urea is only compound generated Other components are all recycled

Answer 346

Transamination reaction to form glutamate

Answer 347

Deaminatiom

Answer 348

HCO3- with ATP

Answer 349

carbamoyl phosphate

Answer 350

carbamoyl phosphate synthase

Answer 351

Citrulline

Answer 352

Ornithine transcarbamylase

Answer 353

Citrulline moves out of mitochondria via a transporter

Answer 354

Aspartate and ATP

Answer 355

Biosynthesis of amino acids, nucleotides and biological amines Excretion

Answer 356

Arginine succinate

Answer 357

Argininosuccinate synthase

Answer 358

Arginine and fumarate

Answer 359

Argininosuccinate lyase

Answer 360

Ornithine and releases urea

Answer 361

Arginase/ornithine aminotransferase

Answer 362

Through the aspartate-argininosuccinate shunt of the TCA cycle

Answer 363

Fumarate produced by argininosuccinate lyase enters the TCA cycle Converted to oxaloacetate Oxaloacetate accepts an amino group from glutamate (transamination) Forms aspartate - leaves mitochondria Donates its amino group to the urea cycle in the argininosuccinate synthetase reaction Intermediates in the citric acid cycle are boxed

Answer 364

Amino group from glutamate (transamination)

Answer 365

Neurotoxicity Ammonia crosses the blood-brain barrier readily. Once inside it is converted to glutamate via glutamate dehydrogenase and so depletes the brain of α ketoglutarate. As ketoglutarate falls, so does oxaloacetate and ultimately citric acid cycle activity stops, leading to irreparable cell damage and neural cell death

Answer 366

Respiratory alkalosis

Answer 367

Removal of lipid soluble xenobiotics/drug metabolites/heavy metals Induce bile flow and secretion of biliary lipids Digestion of dietary fat Facilitates protein absorption Cholesterol homeostasis Anti microbial Induce bile flow and solubilise cholesterol Prevents calcium gallstones and oxalate renal stones

Answer 368

By solubilising lipids and lipid digestion products as mixed micelles facilitating aqueous diffusion across intestinal mucosa

Answer 369

Accelerating hydrolysis by pancreatic proteases

Answer 370

Facilitates dietary absorption/elimination as bile acids are water soluble end products of cholesterol catabolism

Answer 371

Enabling movement from hepatocyte to intestinal lumen

Answer 372

Physicochemical and inducing anti-microbial genes

Answer 373

Water Inorganic electrolytes Organic solutes- bile acids, phospholipids, cholesterol, pigment

Answer 374

2/3 deoxycholic 1/2 lithocholic

Answer 375

2/3 bile acids (primary) -cholic- 1/3 -chenodeoxycholic 1/3 Deoxycholic 1/3 -lithocholic and ursodeoxycholic 1/4 phospholipids Small amounts of cholesterol, bilirubin, proteins

Answer 376

500-600 ml

Answer 377

Synthesised from cholesterol in hepatocytes Converted into cholic acid and chenodeoxycholic acid Enzyme = CYP7A1 Conjugated with glycine/taurine before secretion into bile canaliculi

Answer 378

Increases hydrophilicity Increases acidic strength of the side chain Decreases passive diffusion of bile across cell membranes (keeps it intraluminal)

Answer 379

Presence of intestinal bacteria converts primary to secondary Enzyme = 7 alpha-dehydroxylase

Answer 380

7 alpha-dehydroxylase

Answer 381

Hepatic synthesis and canalicular secretion of bile acids (major organic anion in bile)

Answer 382

Cholic acid Chenodeoxycholic acid

Answer 383

Bile acids travel down biliary tract to the gallbladder where it is concentrated 10-fold

Answer 384

CCK released from duodenal mucosa

Answer 385

Relaxes sphincter of Oddi Contracts gallbladder Releasing concentrated solution of mixed micelles (bile acid, phospholipids, cholesterol)

Answer 386

Conjugated bile acids remain intraluminal Some reabsorbed passively in Jejunum-ileum Actively transported via the apical sodium bile acid transporter in the ileum Re-enters liver via portal circulation Bile acids take up by hepatocytes and re-conjugated secreted into biliary canaliculi

Answer 387

Too much bile acid Ligand for farnisoid X receptor in ileum Results in synthesis of FGF-19 (endocrine polypeptide molecule) Inhibition of CYP7A1 (cholesterol 7 alpha hydroxylase) - first step in converting cholesterol into bile acids

Answer 388

Farnisoid X receptor in ileum

Answer 389

Statins- inhibit HMG CoA reductase

Answer 390

Ezetimibe- stops protein mediated transport across enterocyte membrane

Answer 391

Amino acids —> Acetyl-CoA—> citrate—> acetyl-CoA —> malonyl CoA—> fatty acids

Answer 392

1. Bile acids - CYP7A1 2. Cholesterol esters for storage - ACAT 3. Combine with triglycerides to form VLDLs

Answer 393

IDL (intermediate density lipoprotein) Cells use triglycerides and cholesterol

Answer 394

Loss of cholesterol

Answer 395

Glucagon Cortisol Growth hormone Adrenaline Noradrenaline Thyroid hormone

Answer 396

Reduce surface tension Aid emulsification

Answer 397

unabsorbed bile acids enter colon where inhibit water absorption / induce secretion resulting in ‘bile salt diarrhoea’

Answer 398

daily bile acid secretion is not altered much. Bile is ‘stored’ in proximal small intestine – likely big ‘shift’ to distal small intestine ‘overwhelms’ transport mechanism or feedback mechanism

Answer 399

CBD stone, pancreatic carcinoma – intestinal malabsorption of fat soluble vitamins and fat resulting in steatorrhoea and develop jaundice

Answer 400

bacterial overgrowth- deconjugation of bile acids cholecystectomy ileal resection may result in diarrhoea / steatorrhoea malabsorption of fat soluble vitamins

Answer 401

Alteration of number/composition of bacteria in small intestine Bloating, diarrhoea, abdominal pain Treat with antibiotics

Answer 402

Factor II, VII, IX X

Answer 403

Cholecystokinin CCK- causes contraction of gallbladder but flow of bile is obstructed

Answer 404

Inversely proportional More bile acid reabsorbed— > bile acids recycled and re-secreted via enterohepatic cycle so less bile acids produced

Answer 405

Presence of partially digested fats and proteins in duodenum Cholecystokinin and secretin released CCK acts on gallbladder to secrete bile Secretin stimulates biliary duct cells to secrete bicarbonate and water - expanding volume of bile

Answer 406

Erythrocytes more susceptible to to oxidative stress Increased haemolysis

Answer 407

Liver Spleen Bone marrow

Answer 408

Non-functional glucuronyl transferase

Answer 409

Build up of bile salts

Answer 410

> 21 mmol/L

Answer 411

Conjugated bilirubin

Answer 412

Pre-hepatic

Answer 413

1972: - 10 -9 -7 -2

Answer 414

Kupffer cells

Answer 415

Glucuronyl transferase

Answer 416

Conversion of ornithine to citrulline

Answer 417

Bind to and transport iron