Lipid Metabolism

nutrient lipids

soluble in organic solvents

may serve as an energy source

constituent of cell and organelle membranes

fat-soluble vitamins

corticosteroid hormones

mediators of e- transport (coenzyme Q)

simple lipids

fatty acids (FA)

mono-, di-, tri-acylglycerides (MAG, DAG, TAG)

compound lipids

combined with another molecule, major class

phospholipids, glycolipids, lipoproteins

derived lipids are obtained from simple or compound lipids that still possess the property of lipids (ex. sterols)

fatty acids

important in energy metab, length ranges from 4-24 carbons

saturated, monounsaturated, polyunsaturated

FA notation

Delta: 18:2/\ ^9,12

Omega: 18:2n-6; dbl bonds separated by 3C

fatty acid characteristics

most important nutritionally and functionally are 14+C

palmitic acid (16:0), stearic acid (18:0), oleic acid (18:1) and linoleic acid (18:2) combine for >90% of FAs in the american diet

fat deficient diet → delayed growth, dermatitis, kidney lesions, early death

essential FAs

linoleic acid and a-linolenic acid

only found in plants (vertebrates cannot desaturate past delta 9 carbon, lack delta12 and delta15 desaturase)

vertebrates can further desaturate 18:2delta9,12 (18:2n-6) in the delta 6 position

FAs can elongate in increments of two carbons

lipid: functions

supply metabolic energy by oxidation of FA to CO2

structural component of cell membranes (phospholipids/sphingolipids)

lubricants

signaling molecules: regulatory roles in metabolism

lipid metabolism: fed

lipid metabolism: fasted

TAG metabolism

de novo FA synthesis

glu → pyruvate, transported to mitochondria

acetyl-CoA formed via PDH complex

acetyl CoA is substrate for citrate

citrate transported back to cytoplasm

acetyl CoA → palmitate (16:0) (de novo FA synthesis)

first and rate limiting reaction is carboxylation of acetyl CoA to malonyl CoA by acetyl CoA carboxylase (ACC)

down regulated by

• palmitoyl CoA (endproduct regulation)

• phosphorylation of the enzyme

up regulated by

• citrate (allosteric)

• dephosphorylation of the enzyme (influenced by insulin:glucagon)

FA synthase (FAS) (de novo FA synthesis)

second and final committed step in FA synthesis

FA synthesis from acetyl CoA and malonyl CoA

FAS catalyzes a series of reactions

• v large polypeptide that includes an acyl carrier protein (ACP)

• ACP: carrier of acyl intermediates during fatty acid synthesis

control - low in fasted state, increases in fed state

substrates of one palmitate (16:0) molecule by FA synthase

7 malonyl CoA

1 acetyl CoA

14 NADPH

14 H+

FA elongation

occurs in ER +/or mitochondria

ER enzymes lengthen FA produced by FAS as well as dietary polyunsaturated FA

involves condensation of acyl CoA groups with malonyl CoA → product is 2 C longer

• catalyzed by Fatty Acid Elongases

FA desaturation

occurs in ER membranes

involves 4 fatty acyl desaturase enzymes (delta 9,6,5, and 4) and delta 4 fatty acyl-CoA desaturase

mammals cannot incorporate a dbl bond beyond delta 9, plants can

FA synthesis hormonal control

insulin - high in fed state, up regulates FA synthesis

glucagon - high in fasted state, down regulates FA synthesis

FAs: inflammation, disease, immunity

FAs are crucial to the immune system - provide structural basis of cell membranes, act as signaling molecules, provide major energy substrate

FA-derived eicosanoids contribute to the inflammatory response

• n-6 PUFA → arachidonic acid: precursor of most important pro-inflammatory eicosanoids

• n-3 PUFA derivatives, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) metabolites are considered less inflammatory

eicosanoids

prostaglandins (PG), thromboxanes (TX), leukotrienes (LT) and lipoxins (LX)

produce a wide range of biological effects

• on inflammatory responses

• on the intensity and duration of pain and fever

• on reproductive function

• important roles in —| gastric acid secretion, regulating BP through vasodilation and constriction, and —| or +→ platelet aggregation and thrombosis

equine exercise induced pulmonary hemorrhage (EIPH)

TAG synthesis

main storage of FAs in body

esters of glycerol (backbone) and 3 FAs

substrates: glycerol-3-phosphate and fatty acids

most FA synthesized or ingested have two fates

• incorporated into triacylglycerols for the storage of metabolic energy (in all cells, predominantly in adipocytes)

• incorporation into the phospholipid components of membranes

TAG function

storage of metabolic energy

high energy content

synthesized from excess carbohydrates

liver, intestine, and adipose most active

sources of glycerol-3-phosphate

dihydroxyacetone phosphate (glycolytic/gluconeogenic intermediates)

glycerol (recycled by liver)

fatty acid sources

de novo synthesis

hydrolysis of TAG in cell

FA from circulation (diet)

monoacylglycerol pathway

TAG catabolism

hormones signal the release of FA from adipose tissue (insulin, glucagon, epinephrine)

FA are metabolized from adipocytes in response to hormone messengers

• adipose triglyceride lipase (ATGL) - rate limiting, induced by PPAR agonists, glucocorticoids, fasting

• hormone sensitive lipase

• monoacylglyceride lipase

overview of FA degredation

FA released from adipose into circulation bound to albumin

dissociation of FA from albumin is first step of cellular uptake

uptake of fatty acids by cells involves membrane proteins

• fatty acid translocase (FAT/CD36)

• plasma membrane associated fatty acid binding protein (FABPpm)

• at least six fatty acid transport proteins (FATPs)

B-oxidation of FA

cyclic degradative pathway

• 2C units (acetyl CoA) cleaved from carboxyl end

• RXN 1: acyl CoA dehydrogenase

• products of 1 cycle: acetyl CoA, 1 FADH2, 1 NADH

FA oxidation energy considerations

palmitate (16:0)

• 7 carbon cleavages: 7×5=35 ATP

• 8 acetyl CoA oxidized: 8×12=96 ATP

• total ATP = 131

• 2 ATP req. for activation

• NET ATP = 129

Unsaturated produce less ATP (dbl bonds require extra enzymes)

odd numbered FA - produce less ATP (last one → propionyl CoA → extra steps to enter TCA cycle)

ketogenesis

during high rates of fatty acid oxidation, primarily in the liver, large amounts of acetyl CoA are generated (build up)

exceeds capacity of TCA cycle

• synthesis of ketone bodies

• ex. acetoacetate, B-hydroxybutyrate, acetone

production is low during normal conditions, increases during CHO shortage

untreated IDDM is most significant disruption

• dec. glu supply (present by can’t be uses in cells)

• inc in FA oxidation

• inc production of acetyl CoA leads to ketone body production in excess of peripheral tissue ability to oxidize them

sources and fates of acetyl CoA

sources

• oxidative decarboxylation of pyruvate from glycolysis

• oxidation of long chain fatty acids

• oxidative degradation of certain AAs

fates

• fatty acid synthesis

• ketone body/cholesterol synthesis

• oxidation in TCA cycle

lipid metabolism - fed

dietary fat (triglyceride) hydrolyzed to FFAs and glycerol in the intestine by pancreatic lipase (PL)

• SCFA can enter circulation directly

• most are re-esterified in epithelial cells and incorporated into chylomicrons

triglycerides in chylomicrons can be cleared by lipoprotein lipase at endothelial surfaces of capillaries (liver, muscle, adipose), resulting FAs can be

• stored as fat in adipose tissue

• used for energy

• reesterfied to triglycerides in the liver and exported as VLDL

VLDL has essentially the same fate as chylomicrons

insulin stimulates

• lipoprotein lipase

• fatty acid and triglyceride synthesis in liver and adipose

insulin inhibits adipose triglyceride lipase/hormone sensitive lipase

lipid metabolism - fasted

glycogen breakdown → glucose; protein breakdown → alanine which is converted to glu in the blood

• blood glu used by brain and RBC

• other tissues rely primarily on FAs as energy source, exercising muscle uses both FAs and glu

hormone sensitive lipase is activated by glucagon (fasting) or epinephrine (exercise); fat in adipose tissue is hydrolyzed to give glycerol and FAs during fasting and exercise

FAs can be used directly as an energy source by most tissues with mitochondria

glycerol can be converted to glu in the liver (minor glu source)

glucagon and epinephrine stimulate hormone-sensitive lipase and inhibit lipoprotein lipase, FA synthesis and triglyceride synthesis

during prolonged starvation, the FAs can also be converted to ketone bodies in the liver, brain adapts slowly to the use of ketone bodies during prolonged starvation

hepatic lipidosis

normal liver contains ~5% lipid (TAG, FA, PL, cholesterol, and chol esters)

hepatic lipid arises from multiple sources - diet, mobilization of peripheral fat stores, endogenous FA synthesis in the liver

if the rate at which FA are brought to the liver exceeds the ability to metabolize or excrete them back into the circulation, storage of FA as TAG (lipidosis) occurs

what leads to it?

• inc delivery of FA to the liver

• dec hepatic FA oxidation

• dec ability to secrete VLDL back

causes

• starvation, diabetes, obesity, drug injury, toxicities

• idiopathic feline lipidosis

idiopathic feline lipidosis

overwhelming majority of cases with severe, clinically apparent liver failure, the cause other than the association with starvation is unknown

often fatal

in starvation

• lack of availability of dietary glu causes increases in growth hormone secretion and sympathetic activity, decreased insulin release

• leads to accelerated peripheral lipolysis and massive free FA release into the circulation

• FAs are taken up by the liver and converted to triglycerides

hypothesis - arginine deficiency, carnitine deficiency, endocrine abnormalities (related to insulin deficiency)

clinical signs - anorexia (>7d), depression, jaundice, weight loss, muscle wasting, occasional v/d

treatment - supportive fluid/nutritional therapy, tube feeding