Exam 3 MCBD

What happens to citrate when ATP and insulin is high

• Citrate shuffle

• Citrate moves out of mitochondria and into cytoplasm

• Start of fatty acid synthesis

Where does citrate come from

Product of citric acid cycle

What happens to excess glucose

Turns into fat and stored as adipose tissue as triglyceride

Triglyceride

Glycerol + 3 fatty acids

Saturated fatty acid

• No double bonds

• Packed tightly

• Linked to clogged arteries

Mono/poly unsaturated fatty acids

• Double bonds create kinks

• Packed loosely

Linolenic acid

• Essential

• Precursor of omega-3

• Lowers triglycerides and prevents blood clot formation

Linoleic acid

• Essential

• Precursor of omega-6

• Lowers LDL (low density lipoproteins)

Oleic acid

• Conditionally essential

• Body only makes a minute amount

Arachidonic acid

• Conditionally essential

• Used for prostaglandin synthesis

• Can be made from linoleic acid

Relate FAs to cell membranes

• Essential FAs are structural components of cell membranes (membrane function and stability)

LDL

• Low-density lipoprotein

• Carries cholesterol from the liver to body tissues

• Bad cholesterol (associated with clogged arteries)

Eicosanoids

signaling molecules made from arachidonic acid

COX pathway

A metabolic pathway that produces prostaglandins and thromboxane from arachidonic acid via cyclooxygenase enzymes

Prostaglandins

An eicosanoid signaling molecule made from Arachidonic acid through the COX pathway that helps regulate inflammation, pain, and other body functions

Thromboxane

An eicosanoid made through the COX pathway from Arachidonic acid that helps blood clot formation

How does NSAIDs affects COX pathway

• Inhibit COX

• results in less prostaglandin and less thromboxane

Lipoproteins

• Particle made of lipids + proteins that transports fats thrrough the blood steam

Chylomicron

• A lipoprotein in the Gut/intestine

• Exogenous (fat it carries is from diet alone)

• carried fat is dietary triglycerides

VLDL

• A lipoprotein in the liver

• Endogenous (fat it carries is made by the body)

• Carried fat is triglycerides made by the liver

LPL

• Lipoprotein lipase

• An enzyme on capillary walls used to break down Chylomicrons and VLDLs

• Activated by Apo C-II

• Releases fatty acids into the bloodstream to be delivered to muscle or adipose tissue

Chylomicron remnant

• What remains after its breakdown

• Taken back up by the liver

VLDL remnant

• What remains after its breakdown

• Taken up by the liver

• Can be further metabolized into LDL

LPL or Apo C-II deficiency

• Body can’t breakdown chylomicrons/VLDL

• Chylomicrons accumulate in plasma

• Causes rise in triglycerides

• increased risk of acute pancreatitis (abdominal pain)

Nonalcoholic fatty liver disease (MASLD)

• Imbalance between hepatic TG (triglycerides) synthesis and VLDL secretion

• Linked to obesity and type II diabetes

• Stages: Imflammation → fibrosis → cirrhosis (irreversible) → liver failure

Cholesterol synthesis

• Acetyl-CoA → HMG CoA → Mevalonate → Cholesterol

• Key enzyme is HMG CoA reductase

• Acetyl-CoA can come from beta-oxidation

HMG CoA reductase

• Enzyme used to convert HMG CoA → Mevalonate

• Activated by Insulin

• Inhibited by glucagon and statin drugs

Triglyceride lipolysis

• The breakdown of stored fat so the body can use it

• Lipase breaks down stored adipose triglycerides into glycerol and fatty acids

• Glycerol: travels to liver where its converted to glycerol-3-phosphate (which can enter gluconeogenesis)

• Fatty Acids: undergo beta-oxidation, which breaks them down into Acetyl-CoA (produces ATP)

Beta-oxidation

• The process of breaking down fatty acids into Acetyl-CoA

• Acetyl-CoA enters Citric Acid Cycle (which produces Oxaloacetate that can be used for gluconeogenesis)

• NADH and FADH2 carry electrons to ETC for ATP production

• happens in mitochondrial matrix

Carnitine shuttle

• A transport system that moves long chained fatty acids into the mitochondrial matrix so they can undergo beta-oxidation

• Needed because long chained fatty acids cannot cross membrane on their own

Insulin affect on carnitine shuttle

• Inhibits shuttle

• High insulin means enough E present, so no needed to burn fat

Carnitine/CPT deficiency

• Fatty acids can’t enter mitochondria - beta-oxidation decreases

• Free FA accumulation in blood

• Low ketone bodies (less beta-oxidation means less acetyl-Coa available to make ketones)

• Fasting Hypoglycemia (body can’t use fat for E so keeps burning glucose)

• Symptoms: lethargy, extreme sleepiness, vomiting

when do we make ketone bodies

• During fasting, starvation, prolonged low carbohydrate intake, or uncontrolled diabetes: low insulin, high glucagon/epinepherine

• Excess Acetyl-CoA converted to ketones (after TCA cycle uses what it needs)

where are ketone bodies made

Mitochondria in Liver

2 Acetyl-CoA → acetoacetyl CoA → HMG CoA → acetoacetate

Acetoacetate

• Ketone body

• Used for Energy

• Transported in the blood to peripheral tissues

3-Hydroxybutyrate

• Ketone body

• Used for Energy

• Reconverted to Acetyl-CoA and oxidized by TCA

Acetone

• Ketone body

• Metabolic dead end

• Not used for Energy

• Made spontaneously from acetoacetate and exhaled

Function of ketone bodies

• Alternative fuel source when glucose is low

• Made from Acetyl-CoA (from triglyceride breakdown)

• Brain can’t use fatty acids, but can use ketones because they can cross the blood-brain barrier

Ketone effects on brain

• When there are ketones in the brain, the brain can rely more on ketones than glucose for E source

• Decreased glucose demand → decreased muscle breakdown

• Muscle protein is reserved

Ketosis

Metabolic state where body breaks down more fat and the liver produces ketone bodies for E because carb availability is low

• Happens during fasting, prolonged exercise, or low carb diet

Ketoacidosis

• A dangerous build up of ketones that makes the blood too acidic

• Associated with uncontrolled diabetes

• Signs: extreme thirst, frequent urination

What diseases come from defective lipid metabolism

• Gauchers

• Niemann-Pick

• Tay-Sachs

• Krabbe

Transanimation

• Transfers an amine group to make new non-essential AAs

• requires Vitamin B6

• Enzyme used: Aminotransferase

Deanimation

• Breaks down AA’s and releases toxic amine groups

• Releases ammonia

• Liver converts ammonia into urea through the urea cycle

Urea Cycle

Cycle that converts toxic ammonia into non-toxic urea and excreted as urine

Occurs in liver (partly in mitochondria, partly in cytoplasm)

Enzymes used in Urea Cycle

• Ornithine transcarbamylase (OTC)

• Carbamoyl phosphate synthetase I (CPS I)

• Argininosuccinate synthetase

• Argininosuccinate lyase

What happens when defect in any of the 4 enzymes in the Urea Cycle?

• Results in toxic ammonia (hyperammonia) in system

• Usually noticed in infancy

• OTC defects are the most common urea cycle disorder

Citrullinemia

genetic disorder caused by defected Argininosuccinate synthetase

Reye syndrome

• Associated with urea cycle enzyme deficiency

• Hyperammonemia, liver failure, hypoglycemia, encephalopathy

BUN (blood urea nitrogen) test

• Test to measure urea in blood to assess kidney function/damage and effectiveness of dialysis

Phenylketonuria (PKU)

• AA metabolism disorder

• Affected AA: Phe, Tyr

• Effects: Intellectual disability, microcephaly, decreased skin/hair pigmentation, musty odor

• Treatment: dietary restructions of Phe

Oculocutaneous albinism

• AA metabolism disorder

• Affected AA: Tyr

• Effects: lack of melanin: white hair, very pale skin, light-colored irises

Alkaptonuria

• AA metabolism disorder

• Affected AA: Tyr

• Effects: Dark urine, pigmented sclera (ochronosis)

Cystinuria

• AA metabolism disorder

• Affected AA: Cys

• Effects: Excess urinary cysteine, kidney stones

Homocystinuria

• AA metabolism disorder

• Affected AA: Met

• Effects: Myopia, marfan-like skeletal changes, DVT, intellectual disability, scoliosis

Maple syrup urine disease (ketoacidemia)

• AA metabolism disorder

• Affected AA: Ile, Leu, Val

• Effects: Intellectual disability, ketosis, seizures

Heme synthesis

1. ALA synthase: glycine + succinyl-CoA → ALA (occurs in mitochondria. requires Vitamin B6)

2. ALA dehydratase: Helps convert ALA to next intermediate. (inhibited by Lead)

3. Several steps → protoporphyrin IX

4. Ferrochelatase (heme synthase): Adds Fe2+ to protoporphyrin IX → heme (Inhibited by Lead)

What enzymes does Lead target?

• ALA dehydratase

• Ferrochelatase

Vitamin B6 deficiency

• Affects heme synthesis because vitamin B6 is needed in first step

• Results in sideroblastic anemia: skin rashes, cracked and sore lips, sore and glossy tongue)

Lead Poisoning

• Inhibits ALA dehydratase and ferrochelatase (affects heme synthesis)

• Results in sideroblastic anemia

• Lead line can be seen at the gumline

Iron deficiency

• Affects heme synthesis because iron is used in last step

• Results in microcytic hypochromic anemia

Bilirubin

• A yellow waste product made from old RBC when they are broken down

• Too much can cause jaundice

• Very high levels can cause Kernicterus

Kernicterus

• Caused by very high levels of bilirubin

• damages the brain

• Effects: cerebral palsy, hearing loss, intellectual disability, stains on enamel of primary teeth

• Treatment: Phototherapy, IVIg, exchange transfusion

Steatosis (fatty change) accumulation

• Abnormal fat accumulation in cells (typically liver)

• Often reflects damage to lipid transport

• Seen in alcholism/binge drinking, malnutrition, diabetes, obesity (MASLD)

• Caused by increase FFA synthesis, decrease FA oxidation, decrease lipoproteins

Amyloid accumulation

• Misfolded beta-pleated sheet protein deposited in tissue

• Seen in amyloidosis, multiple myeloma, Alzheimer’s, and some tumors

Anthracosis accumulation

• Inhaled carbon particles stored long term in lung macrophages (air pollution/ smoking)

• Discolors bronchial mucosa black

Lipofuscin accumulation

• “wear and tear” pigment

• insoluble brown particles of oxidized lipid and protein from membrane turnover

• builds up with age and chronic inflammation

Hemosiderin accumulation

• Golden brown, iron-containing pigment from the breakdown of hemoglobin (hemolysis, RBC breakdown)

Pyknosis

Nucleus shrinks (becomes dense with condensed chromatin)

Karyorrhexis

Nucleus fragments/breaks apart

Karyolysis

Nucleus dissolves and fades

Coagulative tissue necrosis

• Tissue architecture is preserved, but cells are dead

• Usually caused by ischemia (loss of blood supply)

• tissue pale but firm

Liquefactive tissue necrosis

• Dead tissue dissolves into liquid

• Common in tissues with many lysosomes (brain)/ bacterial infection

• pus

Caseous tissue necrosis

• Soft, crumbly, cheese-like tissue

• Cell outline lost but not fully lysed

• pink granular debris at center of a granuloma

• Classically seen in TB

Gummatous tissue necrosis

• Dead tissue is rubbery and surrounded by granulomatous inflammation

• noncancerous growth

• seen in syphilis

Hemorrhagic tissue necrosis

• Dead tissue full of RBC

• Often due to venous obstruction while arterial supply remains

Enzymatic fat necrosis

• Pancreatic enzymes (lipases) escape and break down fat into fatty acids

• FA binds to calcium in surrounding tissue

• Forms chalky soap like substances (saponification)

• Ex. acute pancreatitis

Labile tissue

• Constantly dividing

• stem cells readily avaialble

• regenerate after injury as long as enough stem cells remain

• Ex. skin, oral mucosa, gut lining, hematopoietic tissue

Stable tissue

• Normally divide only rarely

• Can be stimulated to divide after injury

• contain progenitor cells for faster renewal

• Ex. glands, liver, kidney, most connective tissue

Permanent tissue

• Terminally differentiated

• Cannot re-enter the cell cycle or regenerate

• heal only by fibrosis (scarring)

• Ex. nerve cells, skeletal muscle, cardiac muscle

Granulation tissue

• A tissue type formed during repair

• Made of proliferating fibroblasts and fragile new capillaries

• Occur during early stages of healing

Granuloma

• A collection of immune cells that walls off something hard to eliminate (focal pattern of chronic inflammation)

• Made of organized clusters of activated macrophages

• Occurs in chronic inflammation (TB, syphilis)

Primary intention

• Describes healing wounds with edges close together (well sutured incision)

• Healing is swift and clean

• minimal scarring

Secondary intention

• Describes healing wounds with edges far apart (wide open with tissue loss)

• Healing is slower. Fills in from the base with granulation tissue

• Scarring is more obvious