IV - Lipids Flashcards
Lipids are hydro___, are soluble in _____ solvents and are compartmentalized to protect themselves for the _____ environment of cells.
hydrophobic, non-polar, watery cytoplasm
Functions of Lipids
major source of energy, provide hydrophobic barries, serve as coenzymes/regulators, hormones, mediators of inflammation
Phospholipids are _____ which enables formation of _____.
amphipathic, bilayers
Long chains of carboxylic acids
Fatty Acids
Fatty acids without double bonds
saturated
Fatty acids with one double bond
monounsaturated
Fatty acids with two or more double bonds
polyunsaturated
Fatty acids that increase risk for cardiovascular diseases
trans- and saturated FAs
Fatty acids that are protective against cardiovascular diseases
mono- and polyunsaturated FAs
Essential Fatty Acids
Linoleic Acid (Omega 6), Linolenic Acid (Omega 3)
Geometric isomer with the carbon moieties on the SAME side of the double bond
Cis fatty acid
Geometric isomer with the carbon moieties on the OPPOSITE side of the double bond
Trans fatty acid
Fluidity decreases with
increasing chain length (more C atoms, increasing saturation (less double bonds)
Becomes essential if linoleic acid is deficient
Arachidonic Acid
Decrease risk for cardiovascular disease by lowering thromboxane production reducing the tendency of platelts to aggregate
Omega Fatty Acids
FA Activation
FA + CoA + ATP → Fatty acyl-CoA + AMP + PPi
FA Activation: Enzyme
Fatty acyl-CoA synthetase
FA Activation: Cofactor
Panthotenic Acid - B5
FA Activation: Energy Use
2 ATP equivalents
Formation of palmitate (16:0)
Lipogenesis, FA Synthesis
Lipogenesis: Location
Cytosol, major: liver and lactating mammary glands, minor: adipose
Lipogenesis: Substrates
1 acetyl CoA, 7 malonyl CoA, 14 NADPH, ATP
Lipogenesis: Product
Palmitate
Lipogenesis: Rate-Limiting Step
acetyl CoA + ATP → malonyl CoA
Lipogenesis: Rate-Limiting Enzyme
Acetyl CoA carboxylase (ACC)
Acetyl CoA carboxylase (ACC) requires
Biotin
Important Steps in Lipogenesis
synthesis of cytoplasmic acetyl CoA, carboxylation of acetyl CoA to malonyl CoA, assembly of palmitate
Lipogenesis: Step 1
synthesis of cytoplasmic acetyl CoA - transfer of acetyl CoA from the mitochondria to the cytoplasm through a CITRATE shuttle in the well-fed state
Lipogenesis: Step 2
acetyl CoA + ATP → malonyl CoA (acetyl CoA carboxylase) - rate-limiting step
Acetyl CoA carboxylase cofactor
Biotin
Acetyl CoA carboxylase activators
insulin, citrate
Lipogenesis: Step 3
assembly of palmitate (fatty acid synthase)
A multienzyme complex that has an acyl carrier protein (ACP) with panthoenic acid as a cofactor
fatty acid synthase
Fatty acid synthase cofactor
Pantothenic Acid (B5)
Synthesizes palmitate from 1 acetyl CoA + 7 malonyl CoA, uses NADPH as a reducing agent
fatty acid synthase
Sequence of Palmitate Assembly
condensation → reduction → dehydration → reduction
Lipogenesis: Activators
citrate (allosteric), insulin (by dephosphorylation and induction of enzyme synthesis)
Lipogenesis: Inhibitors
fatty acyl-CoA (allosteric), glucagon and epinephrine (by phosphorylation and repression of enzyme synthesis)
FAs further elongate in _____ and _____.
SER, mitochondria
Lipogenesis is limited to
16C Palmitate
SER and mitochondria form 22C and 24C FAs for
Sphingolipids
FAs are desaturated in the ___ through mixed function oxidases (cytochrome _).
SER, cytochrome bs
The body can generate double bonds on FA’s but not beyond
Carbon 9
Short/Medium-chain FAs are bound to _____ until they are taken up by cells.
Albumin
Long-chain FAs (>12C) are transported in the bloodstream through _____.
Lipoproteins
FAs are converted to _____ before being stored as triacyglycerols
fatty acyl-CoA (active form)
Ester of trihydric glycerol and fatty acids, main storage form of FA, slightly soluble in water
Triacylglycerol
Coalesce within adipocytes to form oily droplets that are the major energy reserves of the body
Triacylglycerol
Triacylglycerol Synthesis
glycerol 3-P + 3FA → triglyceride
Triacylglycerol Synthesis: Location
liver, adipose
Source of glycerol 3-P in the liver & adipose
DHAP from glycolysis (glycerol 3-P dehydrogenase)
Source of glycerol 3-P in the liver only
phosphorylation of free glycerol (glycerol kinase)
Mobilization of Stored Fats
triglyceride → glycerol 3-P + 3FA (hormone-sensitive lipase + monoacylglycerol lipase)
Hydrolyzes TAGs yielding 2-monoacylglycerol + 2FA
Hormone-Sensitive Lipase
Hormone-Sensitive Lipase activators
glucagon, epinephrine, cortisol
Hormone-Sensitive Lipase inhibitor
insulin
Hormone-Sensitive Lipase can only release fatty acids from ___ and ___ of the TAG stored in fat
Carbon 1, Carbon 3
2-Monoacylglycerol → FA + Glycerol
Monoacylglycerol lipase
Removal of acetyl CoA fragments from the ends of FAs
Lipolysis, β-Oxidation of FAs
Lipolysis: Location
Mitochondria of all cells except neurons, RBCs, testis, kidney medulla
FA Activation: Location
Cytosol
Lipolysis: Substrates
palmitate, 7 NAD, 7 FAD, ATP
Lipolysis: Products
8 acetyl CoA, 7 FADH2, 7 NADH
Lipolysis: Rate-Limiting Step
fatty acyl CoA + carnitine → fatty acyl carnitine + CoA
Lipolysis: Rate-Limiting Enzyme
Carnitine acyltransferase I (carnitine palmitoyl transferase I)
Long-chain FAs have _ carbons and must be shuttles through the inner mitochondrial membrane via _____
> 12C, carnitine shuttle
Short-chain FAs have ___ carbons
2-4C
Medium-chain FAS have ___ carbons
6-12
fatty acyl carnitine + CoA → fatty acyl CoA + carnitine
Carnitine acyltransferase II - inside mitochondrial matrix
Catalyzed by carnitine acyltransferase II
fatty acyl carnitine + CoA → fatty acyl CoA + carnitine
Sequence of Lipolysis
oxidation → hydration → oxidation → thiolysis
FAs with an odd number of carbons will yield
acetyl CoA and propionyl CoA
Propionyl CoA is converted to _____.
succinyl CoA - a TCA Cycle intermediate
Catalyzed by propionyl CoA carboxylase
propionyl CoA + CO2 + ATP → methylmalonyl CoA + ADP + Pi
propionyl CoA + CO2 + ATP → methylmalonyl CoA + ADP + Pi
propionyl CoA carboxylase
Propionyl CoA carboxylase requires
Biotin
Catalyzed by methylmalonyl CoA mutase
methylmalonyl CoA → succinylt CoA
methylmalonyl CoA → succinylt CoA
methylmalonyl CoA mutase
Methylmalonyl CoA mutase requires
Vitamin B12
Oxidizes very long chain FAs (20C, 22C)
Peroxisomes
Oxidizes unsaturated FAs
3,2-enoyl CoA isomerase
Lipolysis yields __ ATP
129 ATP
Carnitine Palmitoyl Transferase I inhibitor
malonyl CoA
Indirectly inhibits lipolysis by activation acetyl CoA carboxylase and increasing malonyl CoA in the cytoplasm
Insulin
Alcohol leady to fat accumulation in the liver called _____ which ultimately leads to _____.
steatosis (fatty liver), cirrhosis
_____ eats up NAD to decrease _____ in the liver.
Alcohol dehydrogenase, lipolysis
Can occur in the newborn and manifest as hypoglcemia from impaired FA oxidation and muscle weakness from lipid accumulation
Carnitine Deficiency
Affects only the liver resulting in reduces FA oxidation and ketogenesis with hypoglycemia
Carnitine Palmitoyl Transferase I Deficiency
Affects skeletal muscle and, when severe, the liver
Carnitine Palmitoyl Transferase II Deficiency
Decreased FA oxidation, profound hypoglycemia during fasting due to lack of ATP for gluconeogenesis, can cause Sudden Infant Death Syndrome (SIDS)
Medium-Chain Fatty Acyl-CoA Dehydrogenase (MCAD) Deficiency
Medium-Chain Fatty Acyl-CoA Dehydrogenase (MCAD) Deficiency treatment and prevention
treatment: IV glucose, prevention: frequent feeding, high carbohydrate and low fat diet
Caused by eating unripe fruit of the akee tree which contains hypoglycin, a toxin that inactivates MCAD and SCAD leading to hypoglycemia
Jamaican Vomiting Sickness
Rare neurologic disorder due to a defect that causes accumulation of phytanic acid from plants which blocks lipolysis, causes neurologic symptoms due to improper myelinization
Refsum’s Disease
Cerebrohepatorenal syndrome from the absence of peroxisomes, liver dysfunction with jaundice, mental retardation, weakness, hypotonia, craniofacial dysmorphism
Zellweger’s Syndrome
Defect in the peroxisomal activation of VLCFA leads to accumulation of VLCFA leading to apathy, behavioral change, visual loss, spasticity, ataxia and death
X-linked Adrenoleukodystrophy
Converts acetyl CoA to ketone bodies
Ketogenesis
Ketogenesis: Location
liver mitochondria
Ketogenesis: Substrate
Acetyl CoA
Ketogenesis: Products
Ketone Bodies (polar): Acetoacetate & β-hydroxybutyrate (can be used as fuel), Acetone
Ketogenesis: Rate-Limiting Step
acetoacetyl CoA + acetyl CoA → HMG CoA
Ketogenesis: Rate-Limiting Enzyme
HMG CoA Synthase
Ketolysis
β-hydroxybutyrate → Acetoacetate → Acetyl CoA
β-hydroxybutyrate → Acetoacetate → Acetyl CoA
Ketolysis
Ketone bodies can serve as fuel for _____ tissues especially during fasting.
extrahepatic
Periheral tissues with mitochondria that can oxidize ketone bodies
skeletal muscle, renal cortex, brain (fasting > 2 weeks)
The liver cannot convert acetoacetate to acetyl CoA since it lacks
succinyl CoA acetoacetyl CoA transferase (thiophorase)
In prolonged starvation and _____, oxaloacetate is depleted for gluconeogenesis.
diabetic ketoacidosis
In alcoholism, excess NADH shunts oxaloacetate to _____.
malate
Seen in uncontrolled DM, starvation and chronic alcoholics
Ketoacidosis
Dehydration, CNS depression, coma, potassium depletion, metabolic acidosis, sweet/fruity odor of breath
Ketoacidosis
A very hydrophobic steroid alcohol with 27 carbons
Cholesterol
Cholesterol is a precursor/raw material for
cell membranes, vitamin D, adrenal hormones, sex hormones, bile salts
Cholesterol has _ fused hydrocarbon rings with an _-membered branched hydrocarbon chain attached to the _ ring.
4 fused hydrocarbon rings, 8-membered branched hydrocarbon chain, D ring
Cholesterol has a single ___ group located at the carbon _ of the _ ring to which FA can be attached to form cholesterol esters.
single hydroxyl group, carbon 3, A ring
Cholesterol Synthesis: Location
SER and cytosol, all cells (mainly in the liver and intestines)
Cholesterol Synthesis: Substrates
acetyl CoA, NADPH, ATP
Cholesterol Synthesis: Products
Lanosterol → Cholesterol
Cholesterol Synthesis: Rate-Limiting Step
HMG CoA → Mevalonate
Cholesterol Synthesis: Rate-Limiting Enzyme
HMG CoA Reductase
Drugs used for the treatment of hypercholesterolemia to reduce the risk for cardiovascular disease, competitive inhibitors of HMG CoA reductase
Statins
Important Steps in Cholesterol Synthesis
biosynthesis of mevalonate, formation of isoprenoid units (isopentenyl diphosphate), 6 isoprenoid units form isoprene, formation of lanosterol, formation of cholesterol
Cholesterol synthesis intermediate used for synthesis of coenzyme Q for the ETC, synthesis of dolichol pyrophosphate (cofactor in N-linked glycosylation of proteins in the RER), prenylation of proteins that need to be held in the cell membrane by a lipid tail
Farnesyl pyrophosphate
HMG CoA reductase inhibitors
glucagon, cortisol, epinephrine, phosphorylation, high cholesterol (limits the transcription factor SREBP - Sterol Regulatory Element-Binding Protein)
Cholesterol rings _____ be metabolized in humans.
cannot
Cholesterol is eliminated though _____ the secreted into the _____.
bile salts, bile
_____ can reduce cholesterol to _____ and _____.
Intestinal bacteria, coprostanol, cholestanol,
Synthesized in the liver from cholesterol
bile acids
Bile Acid Synthesis: Rate-Limiting Step
cholesterol → cholic acid
Bile Acid Synthesis: Rate-Limiting Enzyme
cholesterol-7-α-hydroxylase
Cholesterol-7-α-hydroxylase activator
cholesterol
Cholesterol-7-α-hydroxylase inhibitor
bile acids
Primary Bile Acids
cholic acid, chenodeoxycholic acid
Bile acids conjugated with either glycine or taurine
bile salts
Emulsify lipids in the intestines, provide the only significant mechanism for cholesterol excretion, both as a metabolic product of cholesterol and as a solubilizer of cholesterol in bile
bile salts
Secondary Bile Acids
deoxycholic acid, lithocholic acid
95% of excreted bile is reabsorbed in the _____ through the _____.
terminal ileum, enterohepatic circulation (5% excreted in feces = amount liver must make)
Mineralocorticoids
Zona Glomerulosa
Glucocorticoids
Zona Fasciculata
Sex Hormones
Zona Reticularis
Zona Glomerulosa
Mineralocorticoids
Zona Fasciculata
Glucocorticoids
Zona Reticularis
Sex Hormones
Steroid Hormone Synthesis: Location
SER of adrenal cortex, ovaries, testes, placenta
Steroid Hormone Synthesis: Substrates
cholesterol, pregnenolone (mother enzyme)
Steroid Hormone Synthesis: Rate-Limiting Step
cholesterol → pregnenolone
Steroid Hormone Synthesis: Rate-Limiting Enzyme
desmolase
Desmolase inhibitor
aminogluthetimide
Lingual lipase and gastric lipase are both ___ labile hence they are destroyed in the _____. This is important in _____ who do not have very acidic stomachs.
acid labile, stomach, neonates
In the gut, lipid components become enclosed in _____ then absorbed into _____.
micelles, enterocytes
Mixed micelles contain the products of lipid digestion by _____ and _____.
lipase, cholesteryl esterase
Secreted to lymphatics, reach the capillaries of skeletal muscle and adipose where TGs are broken into FA and glycerol via lipoprotein lipase
Chylomicrons
Directly enter adjacent muscle cells or adipocytes or may be transported in blood bound to albumin
Free Fatty Acids
Converted to DHAP then enters glycolysis or gluconeogenesis
Glycerol
Pancreatic Lipase: Substrate
TAG from diet
Pancreatic Lipase: Product
2-monoacylglycerol (MAG)
Pancreatic Lipase: Activator
trypsin
Lipoprotin Lipase: Substrate
TAG from chylomicrons and VLDL
Lipoprotin Lipase: Product
free glycerol
Lipoprotin Lipase: Activator
insulin
Hormone-Sensitive Lipase: Substrate
TAG from adipose
Hormone-Sensitive Lipase: Product
2-monoacylglycerol (MAG)
Hormone-Sensitive Lipase: Activator
glucagon
Manifests as steatorrhea (greasy stools), deficiency in fat-soluble vitamins and essential fatty acids
Lipid Malabsorption
Lipid Malabsorption causes
liver disease (not enough bile), pancreatic disease (enzyme deficiencies), cholelithiasis (bile obstruction), shortened bowel (decreased absorption time), intestinal mucosal defects
Spherical macromolecular complexes composed of neutral lipid core surrounded by a shell of amphipathic apolipoproteins, phospholiid and nonesterified cholesterol
Plasma Lipoproteins
Keep their component lipids soluble as they transport them in plasma, provides an efficient mechanism for transporting their lipid contents to and from the tissues
Plasma Lipoproteins
Plasma Lipoproteins: Highest in Protein
HDL (50%)
Plasma Lipoproteins: Highest in TG
Chylomicrons (88%)
Plasma Lipoproteins: Highest in Cholesterol
LDL (10%)
Plasma Lipoproteins: Highest in Cholesterol Esters
LDL (48%)
HIghest component of VLDL
TG (56%)
HIghest component of IDL
Cholesterol Esters (34%)
Transports dietary TG and cholesterol from the intestines to the tissues
Chylomicrons
Chylomicron Apoproteins
Apo B-48 (secreted by epithellial cells), Apo C-11 (activates lipoprotein lipase), Apo E (uptake by the liver)
Transports triglycerides from the liver to the tissues
VLDL
VLDL Apoproteins
Apo B-100 (secreted by the liver), Apo C-11 (activates lipoprotein lipase), Apo E (uptake by the liver)
Picks up cholesterol from HDL to become LDL
IDL
IDL Apoprotein
Apo E (uptake by the liver)
Delivers cholesterol into cells
Apo B-100 (uptake by the liver and other tissues via LDL receptor)
Picks up cholesterol accumulation in blood vessels (reverse cholesterol transport)
HDL
Delivers cholesterol to liver and steroidogenic tissues via scavenger receptor (SR-B1)
HDL
Shuttles Apo C-11 and Apo E in blood
HDL
HDL Apoprotein
Apo A-1 (activates lecithin cholesterol acyltransferase or LCAT to produce cholesterol esters)
Activates LCAT
Apo A-1
Binds to LDL and VLDL receptors
Apo B-100
Cofactor for lipoprotein lipase, shuttled by HDLs
Apo C-11
Chylomicron assembly and secretion
Apo B-48
Mediates uptake of chylomicron remnant
Apo E
Deposition of cholesterol and cholesteryl esters in the artery walls especially oxidized LDL, more sever in DM, lipid nephrosis and hypothyroidism
Atherosclerosis
Oxidized LDLs can cause endothelial damage which predisposes to _____.
atherosclerosis
Type I Familial Dyslipidemia
Hyperchylomicronemia
Type II Familial Dyslipidemia
Hypercholesterolemia
Type III Familial Dyslipidemia
Dysbetalipoproteinemia
Type IV Familial Dyslipidemia
Hypertriglyceridemia
Hyperchylomicronemia: Deficiency
Lipoprotein Lipase: high chylomicrons and VLDL, low LDL and HDL
Xanthomas and pancreatitis without increased risk of coronary heart disease
Hyperchylomicronemia
Hypercholesterolemia: Deficiency
LDL Receptors: high LDL
Xanthomas and xanthelasmas with increased risk of atherosclerosis and coronary heart disease
Hypercholesterolemia
Dysbetalipoproteinemia: Deficiency
Apo E: high remnants of chylomicrons and VLDL
Increased risk of atherosclerosis and coronary heart disease without xanthomas
Dysbetalipoproteinemia
Hypertriglyceridemia: Pathogenesis
increased VLDL productin
Triad: coronary artery disease, T2DM, obesity
Hypertriglyceridemia
Apo B-48 and Apo B-100 deficiency
Abetalipoproteinemia: no chylomicrons/VLDL/LDL
Intestinal malabsorption with accumulation of lipids in the intestine and liver
Abetalipoproteinemia
Apo A-1 deficiency
Familial α-Lipoprotein Deficiency (Tangier’s/Fisheye Disease): no HDL
High triglycerides, premature atherosclerosis, neuropathy, enlarged yellow-orange tonsils
Familial α-Lipoprotein Deficiency (Tangier’s/Fisheye Disease)
Increased HDL production
Familial Hyper-α-Lipoproteinemia: associated with benefits to health and longevity
High Lipoprotein A
Familial Lipoprotein A Excess
Early atherosclerosis and thrombosis
Familial Lipoprotein A Excess
Phospholipids are _____ compounds composed of _____, _____ and _____.
amphipathic, alcohol, diacylglycerol or sphingosine backbone, phosphodiester bond
Predominant lipids of cell membranes, degraded by phospholipases
Phospholipids
Most abundant phispholipids
Phosphatidylcholine
Large proportion of body’s store of choline, important in nervous transmission (acetylcholine), store of labile methyl groups
Phosphatidylcholine
Plays a role in apoptosis, also found in cell membranes
Phosphatidylethanolamine (cephalin) and Phosphatidylserine
Major component of lung surfactant, deficiency leads to RDS
Dipalmitoylphosphatidylcholine (DPPC) or Dipalmitoyllecithin
Reservoir for arachidonic acid in membranes, source of 2nd messengers
Phosphatidylinositol
2 molecules of phosphatidic acid esterified through their phosphate groups to an additional molecule of glycerol
Cardiolipin
Found only in mitochondria and is essential for mitochondrial function
Cardiolipin
Deficiency or defect can cause mitochondrial dysfunction in aging and in heart failure, hypothyroidism and Barth syndrome (cardioskeletal myopathy)
Cardiolipin
_____ is antigenic. It reacts with antibodies produced against Treponema pallidum (syphilis). One of the non-treponemal tests for syphilis is an anti-_____ test.
Cardiolipin
Part of the glycocalyx located on the outer layer of the cell membrane and functions in cell recognition and adhesion, found in high concentrations in nervous tissue
Glycolipids
Ceramide
Sphingosine + Fatty Acid
Cerebroside
Ceramide + Glucose or Galactose
Globoside
Ceramide + Oligosaccharide
Ganglioside
Ceramide + N-acetylneuramic Acid
Sulfatides
Ceramide + Sulfatide Galactose
Sphingosine + Fatty Acid
Ceramide
Ceramide + Glucose or Galactose
Cerebroside
Ceramide + Oligosaccharide
Globoside
Ceramide + N-acetylneuramic Acid
Ganglioside
Ceramide + Sulfatide Galactose
Sulfatides
The only significant sphingophospholipid in humans, an important constituent of the myelin sheath in nerves
Sphingomyelin
Deficiency in phospholipids and sphingolipids from white matter resulting in increased CSF phospholipids
Demyelinating Diseases
Lipid storage diseases often manifested in childhood, lipid synthesis is normal, lipid degradation in lysosomes is abnormal
Sphingolipidoses
Complex lipids accumulate in cells, neurodegeneration, enzyme deficiency is similar in all tissues
Sphingolipidoses
Tay-Sach’s Disease: Deficiency
Hexosaminidase A
Tay-Sach’s Disease: Accumulating Lipid
Ganglioside
Tay-Sach’s Disease: Findings
cherry red macula, mental retardation, hypotonia
Hexosaminidase A Deficiency
Tay-Sach’s Disease
Fabry’s Disease: Deficiency
α-Galactosidase
Fabry’s Disease: Accumulating Lipid
Globotriaosylceramide
Fabry’s Disease: Findings
3 Rs: Recessive (X-linked), Rash, Renal failure
α-Galactosidase Deficiency
Fabry’s Disease
Gaucher’s Disease: Deficiency
β-Glucosidase
Gaucher’s Disease: Accumulating Lipid
Glucosylceramide
Gaucher’s Disease: Findings
hepatosplenomegaly, erosion of long bones, Gaucher cells: accumulation of fibrils in macrophage, crumpled tissue paper
β-Glucosidase Deficiency
Gaucher’s Disease
Niemann-Pick Disease: Deficiency
Sphingomyelinase
Niemann-Pick Disease: Accumulating Lipid
Sphingomyelin
Niemann-Pick Disease: Findings
hepatosplenomegaly, foam cells: small vacuoles, lipid-laden macrophages, sea-blue histiocytes
Potents compunds that elicit a wide range of physiologic and pathologic responses
Eicosanoids
3 Main Kinds of Eicosanoids
prostaglandin, thromboxane, leukotriene
Eicosanoids: Dietary Precursor
Linoleic Acid
Eicosanoids: Immediate Precursor
Arachidonic Acid
Released from membrane lipids by phospholipase A2
Eicosanoids
Synthesized by platelets, causes vasoconstriction and platelet aggregation
Thromboxane (TXA2)
Produced by blood vessel walls, inhibitors of platelet aggregation
Prostacyclin (PGI2)
mixture of leukotrienes C4, D4 and E4, potent bronchoconstrictors
Slow-Reacting Substances of Anaphylaxis (SRS-A)
Slow-Reacting Substances of Anaphylaxis (SRS-A)
Leukotrienes C4, D4 and E4
All sphingolipidoses are _____ recessive except _____.
autosomal recessive (sphingolipidoses), Fabry’s Disease (X-linked recessive)
