made of phosphatidic acid (an intermediate from triacylglycerol biosynthesis)

most common phospholipid

made in most cells of the body

Diacylglycerol+CDP-Choline=phosphatidylcholine

CDP-diacylglycerol+inositol=phosphatidylinositol

note: CDP must come from somewhere

phosphatidylserine->phosphatidylcholine (in liver)

actions of PLA1 and PLA2 can add/remove to fatty acyl

PLA2/PLC also act in cell signaling

PLA2 releases arachidonic acid from membrane

Sphyngomyelin

Ceramide

most common in CNS

ceramide: basic unit of sphingolipids

Sphingosine+phosphatidylcholine->sphingomyelin

(PC) is part of lung surfactant

has 2 saturated residues (DPPC)

prevents lung colapse

less than 24 weeks, mostly sphingomyelin. 35 weeks become DPPC

adult resperatory distress syndrome: surfactant secreting alveolar type II pneumocites destroyed

mediate inflamation/hemostasis/muscle contraction/BP

produced in cells, used as needed (not stored)

made of arachidonic acid

COX pathway

lipoxygenase pathway

COX: Arachidonic acid->prosteglandin(PGs) + thromboxanes(TXs)

PGI1: inhibit platelet clumping,cause vasodilation

TXA2: stimulate platelet clumping,cause vasoconstriction

PGF2: stimulate uterine contraction during birt

Lipoxygenase: arachidonic acid->leukotrienes(LTs)

LTC/LTD/LTE: parts of SRS-A.  cause bronchoconstriction/vasoconstriction/increas vascular permiability

NSAIDS

NSAIDS: inhibits COX1 and COX2

selective COX2 inhib: celecoxib(celebrex) stops inflamation (viox and bextra taken out)

sugar-containing derivitives of ceramide

found most in nerve tissue as cell membrane

used for communication

(eg) antigens (ABO), or receptors for bacterial toxins

lysosomal storage diseases

Niemann-Pick A/B

which enzyme damaged?

what lipid buildup?

symptoms?

Nieman-Pick: lacks enzyme sphingomyelinase

can't convert sphingomyelin into ceramide

acumulates sphingomyelin

symptom: hepatosplenomegaly/retardation (type A)

Lysosomal Storage Disease

Fabry

what enzyme damaged?

what lipid buildup?

what symptoms?

damage: α-galactosidase. 

cant turn Gal-Gal-Glc-Cer into Gal-Glc-Cer

buildup of Gal-Gal-Glc-Cer (globosides)

Symptoms: skin rash/kidney & heart failure

treated with Fabrazyme

Lysosomal Storage Disease

Gaucher

what enzyme damaged?

what lipid buildup?

what symptoms?

most common lysosomal storage disease

damage to β-glucosidase

cant convert glucocerebroside into ceramide

buildup of glucosylceramde (glucocerebrosides)

symptoms: hepatosplenomegalt, osteoperosis of long bones

treated with cerezyme

Lysosomal Storage Disease

Tay-Sachs

what enzyme damaged?

what lipid buildup?

what symptoms?

lacks β-Hexosaminidase A

cant turn GM2 Ganglioside into GM3 Ganglioside

buildup of GM2 Ganglioside

Symptoms: retardation, muscular weakness, red macula, blindness

13 nobel prizes

complex 4 ring structure

synthesized from a 2 carbon substrate

essential function in membranes of animal cells

makes hormones and bile acids

forms plaques resulting in MI and strokes

3 Acetyl CoAs-> HMG CoA

reduction of HMGCoA to Mevalonate (rate limiting).

converting Mevalonate into cholesterol by isoprenoid intermediates

occurs in liver cytosol

Acetyl CoA from pyruvate or fatty acids

phosphorylate HMGCoA reductase = inactivated

AMP levels (inactivates)

hormones insulin (activates)/glucagon (inactivates)

(at golgi)

S2p and S1p triggers SCAP to release SREBP to nucleus

HMG CoAR releases to raise cholesterol

at ER, cholesterol causes NSIG-SCAP-SREP complex to conformational change, so complex stays at ER

when no cholesterol, SCAP released from complex, and travels to Golgi

inhibits FPP synthesis farnesilation

decreases osteoclast mediated breakdown of bone

cholesterol 7α-hydroxylase catalizes rate limiting

high cholesterol increases, bile reduces

after synthesis in liver, primary bile acid conjugated by gly or tyrene

Cholesterol+enzyme->CholylCoA

CholylCoA+Glycine=glychocolic acid (bile salt)

due to lack of bile salts in bile causes cholesterol precipitation

making steroids

where

rate limiting

in adrenal cortex/testes/ovaries

rate limiting: cholesterol-> pregnenalone by mitochondrial desmolase.

pregnalone->progesterone

steroid hormone synthesis diseases

Cushing's syndrome

Addison's disease

congenital adrenal hyperplasia

Cushing's: excess adrenal synthesis of cortisol

Addison's: adrenal insufficiency

CAH: overproduction of androgen

transfered as lipoproteins (amphipathic)

Chylomicrons: triglycerides

LDL(bad) HDL(good)

HDL

"borrowed cholesterol transport"

transports excess cholesterol to liver for excretion

ABCA1:transport protein

LCAT: esterifies cholesterol to keep unidirectional movement of cholesterol

APP A1: activates LCAT

Familial Combined Hyperlipidemia

Familial Hypercholesterolemia

Polygenic Hypercholesterolemia

(FCH)

leads to heart disease

overorduction of APOB-100 containing proteins

(FH)

less LDL receptors, so more LDL in blood

polygenic

non familial, leading cause of Hight cholesterol

pharmacological regulation of cholesterol

HMG CoA reductase inhib

Bile acid binding resins

Ezetamide

Nicotinic Acid

Fibrates

HMG COA Reductase inhib: increase liver clearance of LDL, combo with ezetamide

Bile Acid binding resins: binds bile salts, prevent reabsorption, lowers lipid absorption, increase liver clearance of LDL

Ezetamide: acts on intestne&liver, inhibits NPC1L1 uptake of cholesterol, increase cholesterol loss in bile, combo with symvastatin

Nicotinic Acid: lowers liver synthesis of VLDL

Fibrates: inhibits liver synthesis of VLDL

phosphorylate

inhibit

low

high

Stomach: Hcl denatures protein, pepsinogen also breaks down proteins

SI: Bicarb neutralizes PH, Trypsin/chimotripsin/elastase breaks protein bonds.  smaller pieces hydrolyzed by exopeptidase

transported through brush borders into intestinal epithelial

dipeptides hydrolized into AA

single AA released into circulation

1 remove amino group

2 amino becomes amonia and aspartate

3 use amonia and aspartate to make urea for scretion

1 α-amino group transfered to α-ketogluterate to make α-ketoacid and glutamate

reversible

caried out by vitamin B6 dependent aminotransferases.  aminotransferases specific to AA

glutamate can send amino group to oxaloacetate to make aspartate (enzyme AST)

or removed to make amonia (enzyme glut D)

release amonia for urea cycle

catalized by glutamate dehydrogenase

glutamate can use either NAD or NADPH

negative effectors: ATP/GTP

Posative effectors: ADP/GDP

amonia from glutamate

CO from bicarb

made in liver, sent to kidney

aspartate->urea and fumerate

low PH: secrete more NH4

high PH: secrete more NH3

BUN (urea in blood) decreases

amonia in blood increase b/c liver not removing it for glutamate synthesis and urea synthesis

NH3 is substrate of urea synthesis, so urea synthesis goes up, also high P causes proteins/ezymes to work quicker

High PH: secrete more urea

low PH:secrete less urea, more NH4, so bicarb not used for urea, so can combo with acid to make C02

AA breakdown

4 carbon oxidized AA

4 carbon reduced AA

5 carbons in a row

3 carbons

4 oxidized: oxaloacetate

4 reduced: succinyl

5: ketogluterate

3: pyruvate

reduced folate=folic acid

folate needed for mitosis, cofactor for enzymes to add a c from AA t purine/pyr

folate and B6 needed for methylation

methylation of DNA=activate DNA for mitosis

PKU

deficient of phenylalanine hydroxylase

cant turn phenylalanine->tyrosine

MSD

lack of branched chain α-ketoacid dehydrogenase

cant release leucine/valine so plug AA in brain cell=adema/coma

irreverseable

acounts for 31%

1.) G6P->6-phosphogluconolactone by G6PD (rate limiting).  NADPH competatively inhibits G6PD

2.) 6-phosphogluconolactone->6-phosphogluconate by 6-phosphogluconolactone hydrolase

3.) 6-phosphogluconate->R5P by 6-phosphogluconate dehydrogenase

net = G6P->1 R5P and 2 NADPH

reversible

acounts for 69%

turns R5P<->F6P and glyceraldehyde-3-P (glycolitic intermediates)

cell doing reductive biosynthesis,no division: NADPH

6 glucose->12 NADPH (when no R5P needed)

cell devides, no reduction biosynthesis: R5P

5 G6P->6 R5P (no NADPH made) ATP consumed in glycolysis

used as an antioxident

also makes superoxides to help WBC kill bacteria

used to make NO to help WBC kill bacteria

Enzymatic: catalase and Glutathione peroxidase (more important), needs NADPH

non-enzymatic: Vitamin C/E, G-SH

class 1-4 higher class more extreme

sex linked, biggest effect on RBC

hemolitic anemia when oxidative stress.

low G6P causes hemolysis b/c WBC eats un-ID RBC

occurs in perivenous liver cells

doesnt use ATP

oxidative phosphorylation doesnt deal with NADPH

Digestion

Stomach:

Small Intestine:

Stomach: Mechanical breakdown, important for infants breakdown milk.  adults breakdown 10-30% here.

Lingual Lipase & gastric Lipase hydrolize short to medium fatty acids.

Small Intestine: gut endocrine cells release:

Secretin: causes pancreas to release bicarb to neutralize PH

CCK: stimulates pancrease to releas digestive enzymes (pancretic lipase/cholesteryl ester hydrolase/phospholipase A2) and bile, and decreas motility, so less food goes into SI

Emulsification

Mediated by bile salts made from cholsterol

surfactant to break clumps into small pieces, with help from pancreatic lipase

--------------------------->2fatty acids+2monoacylglycerol

pancreatic lipase + colipase

------------------------> fatty acid + cholesterol

cholesteryl ester hydrolase

--------------------------------> Fatty acid + LysoPC

phospholipase A₂

fat products  combine w/ bile salts to make micells

hydrophobic & bile salts are in mycells, phylic outside

mycells can pass through brush border lumen enterocyte

free fatty acids are activated by conjugation with CoA "fatty aceyl-CoA synthesis"

shipped out in lipoprotein particles (chylomicrons) into lymphatic system -> blood.

ALLI

fat not absorbed in intestine

inhibits pancreatic lipase

decreases absorption of triglycerides

Questran

fat not absorbed in intestine

binds bile salts, preventd reabsorption

increases body clearance of LDL-cholesterol

Zetia

acts at intestine and liver through enterohepatic circulat

inhibits NPC1L1-mediated uptake of cholesterol by enterocytes

increase loss of cholesterol in bile

combined with simvastatin

triacylglycerols (triglycerides)

Phospholipids

Triglycerides: 90% of fats.  fuel reserves.  oxidation = acetyl CoA, FADH₂, NADH.

Phospholipids: structural for membranes, and signaling

starvation, phospholipids  metabolized into water soluble ketones

FATP-4

NPC1L1

SR-B1

ABCG5

ABCG8

Lipid Malabsorption

loss of lipids in feces (steatorrhea)

Cystic Fibrosis

Celiac Disease

Crohn's disease

Cholelithiasis

Cystic Fibrosis: most common fatal genetic disease in US.

acumulation of mucous causes pancreas insufficiency, lipid malabsorption. 

treat: high protein/med/high fat diet.  enteric pancreatic enzymes

Celiac: damaged intestine mucosa by glutten protein

Crohn's: inflamation of intestinal mucosa

Cholelithiasis: gallstones

in liver, lactating mammary, some in kidney adipose

citrate shuttle exports acetyl CoA out of mitochondria

carboxylation of acetyl CoA to malonyl CoA= rate limiting

synthesis needs ATP& NADPH

acetyl changed to Citrate to exit mitochondria, (an intermediate form of of TCA cycle) in cytoplasm, cytrate cleaved by citrate lyase to regenerate acetyl CoA.

occurs when mitochondrial citrate is high (high ATP)

carboxylation of Acetyl CoA

rate limiting

Acetyl CoA + ATP-----ACC---> Malonyl CoA +ADP + P

biotin dependent

ACC allosteric regulation by citrate (+)& long chain acyl CoA (-)

phosphorylate/de by insulin (act),glucogon,EP (inact)

AMP-activated protein Kinase (inact)

made from Acetyl CoA

Palmitic Acid can be elongated/desaturated. 

catalized by enzymes in the ER

can add double bonds at C 4 5 6 9.

Essential Fatty Acid: linoleic acid because = at c 9,12,15

2 activated fatty acids are added to a glycerol phosphate

a phosphate group is removed, and a 3rd fatty acid is added to make triacylglycerol

triacylglycerols form lipid droplets for energy storage. 

made in liver, incorperated into LDL for export

activate enzyme HSL to remove first fatty acid from triacylglycerol

other lipases break off another fatty acid

Free Fatty Acids (FFA) enters blood, bind to albunun to go to organs/tissue

regulation of lipolysis and release of FFA

INSULIN

EP

Perilipin

Glyceroneogenesis

Insulin: fasting=low insulin=disinhibits HSL activity

EP: promotes HSL through cAMP-mediated phosphorylat

Perilipin: protein on surface of lipid droplets, limits HSL access to tryglycerides. HSL can work if perilipin phosphorylated, so falls off of droplet.

Glyceroneogenesis: 30-40% released FFA reesterified to glycerol within adipocyte.

brings long chain fatty acyl CoAs

Malonyl CoA regulate the shuttle

Carnitine Acyltransferase 1: brings long chain fats into intermembrane mitochondria space

Carnitine Acyltransferase 2 brings them into matrix

oxidation-hydration-oxidation-thiolysis

removes acetyl parts of fatty acid

makes FADH2 and NADH

1 palmitoyl CoA makes net 129 ATP

alternate fatty acid oxidation

Peroxisomes:

ER (Microsomal)

Peroxisomes: verry long chain fatty acids, α β oxidation (no net ATP).  smaller pieces sent to mitochondria

ER: Omega oxidation, cytochrome P450, dicarboxylic acids

AMP activates AMPK (means high energy present)

high AMP activates AMPK by

Allosteric activation, phosphorylation, inhibit dephos

AMP also regulates digestive enzymes, regulates food intake.

MCAD deficiency

medium chain acyl CoA Dehydrogenase

blood medium chain fats go up

glucose in blood goes down

ketone bodies go down

severe hypoglycemia