LIPIDS Flashcards
IMPORTANT FATTY ACIDS
FA naming
ACTIVATION OF FATTY ACIDS
- A fatty acid must be converted to its activated form before it can participate in metabolic processes
- Enzyme: Fatty acyl CoA synthetase
- Occurs in the cytosol
Activated FA: Acyl-CoA
End product of mammalian FA synthesis (Lipogenesis)
Palmitic acid
rate liming step of Lipogenesis
Acetyl CoA + HCO 3 – + ATP → Malonyl CoA
Enzyme: Acetyl CoA carboxylase
Substrate and product of Lipogenesis
Acetyl CoA
Palmitoyl CoA
Citrate Shuttle
*Mitochondrial acetyl CoA (from the oxidation of pyruvate) is transported to the cytosol using the citrate shuttle
Activators of Acetyl-CoA Carboxylase (rate-limiting enzyme of Lipogenesis)
Citrate and Insulin
Inhibitors of Acetyl-CoA Carboxylase (rate-limiting enzyme of Lipogenesis)
Glucagon and epinephrine
Sources of NADPH for Lipogenesis:
- Pentose phosphate pathway
- Malic enzyme
- Isocitrate dehydrogenase
Sequence of steps repeated seven times for Elongation of PAlmitoyl COA (Lipogenesis)
Condensation → Reduction → Dehydration → Reduction
“CoRe DR
Fatty acids are stored as ______
TRIACYLGLYCEROL
Enzyme that breaks down TAG to Glycerol and Fatty Acids
Hormone Sensitive lipase
Beta Oxidation / Lipolysis
- Removal of acetyl CoA fragments from the ends of fatty acids, also yielding NADH and FADH2 in the process
- Acetyl CoA can enter the citric acid cycle
- NADH and FADH 2 can enter the ETC
Substrate for Lipolysis
Palmitate
What are the products of Lipolysis?
8 Acetyl CoA, 7 NADH, 7 FADH 2
Rate limiting step of BETA-OXIDATION or LIPOLYSIS.
Translocation of fatty acyl CoA from the cytosol to the mitochondria
Enyzme: Carnitine-palmitoyl transferase
How many NADPH are consumed in LIPOGENESIS
14
What shuttle is used in Beta oxidation?
Carnitine shuttle
TRANSPORT OF FATTY ACYL COA TO THE MITOCHONDRIA
- Fatty acyl synthetase activates the fatty acid
- Carnitine acyltransferase-1 attaches fatty acyl to carnitine in the outer mitochondrial membrane
- Fatty acyl-carnitine is shuttled through the inner membrane
- Carnitine acyltransferase-2 transfers fatty acyl group back to a CoA in the mitochondrial matrix
Sequence of steps repeated seven times in Beta Oxidataion/Lipolysis:
Oxidation → Hydration → Oxidation → Thiolysis
Enzymes collectively known as fatty acid oxidase in Lipolysis.
“DeHyDeThy”
o Fatty acyl CoA dehydrogenase
o Δ2 enol CoA hydratase
o 3-hydroxyacyl-CoA dehydrogenase
o Thiolase
ATP YIELD of PALMITATE
produced only during beta oxidation of odd-numbered fatty acids (because beta oxidation removes 2 carbons at a time.
Propionyl CoA
Differentiate Lipogenesis from Beta Oxidation
- Leads to decreased oxidation of fatty acids with 6–10 carbons
- Most common inborn error of fatty acid oxidation o Autosomal recessive disorder with a higher incidence in Northern Europeans
MEDIUM-CHAIN FATTY ACYL COA DEHYDROGENASE (MCAD) DEFICIENCY
o Severe hypoglycemia
o Accumulation of fatty acids (dicarboxylic acids) in the urine
o Can manifest as Sudden Infant Death Syndrome (SIDS)
CARNITINE-PALMITOYL TRANSFERASE I DEFICIENCY
- Affects the liver
- Reduced fatty acid oxidation, leading to severe hypoglycemia, coma, and even death
CARNITINE-PALMITOYL TRANSFERASE II DEFICIENCY
- Affects primarily cardiac and skeletal muscle
- Cardiomyopathy, muscle weakness with myoglobinemia after prolonged exercise
- Caused by eating the unripe fruit of the akee tree
- The toxin hypoglycin inactivates medium- and short-chain acylCoA dehydrogenase, inhibiting β-oxidation and causing hypoglycemia
JAMAICAN VOMITING SICKNESS
• Deficiency of phytanoyl-CoA hydroxylase leads to accumulation of phytanic acid
REFSUM DISEASE
o Peripheral neuropathy and ataxia, retinitis pigmentosa, and abnormalities of skin and bones
Accumulation of phytanic acid blocks β-oxidation.
- Cerebrohepatorenal syndrome
- Inherited absences of peroxisomes in all tissues leads to marked accumulation of very-long-chain, saturated, unbranched fatty acids in liver and central nervous system
ZELLWEGER SYNDROME
- Liver dysfunction with jaundice
- Marked mental retardation, weakness, hypotonia
- Craniofacial dysmorphism (high forehead, shallow orbits, hypertelorism, high arched palate, abnormal helices of ears, retrognathia)
- Early death
Inability to transport VLCFAs across the peroxisomal membrane leads to accumulation in the brain, adrenals, and testes
ADRENOLEUKODYSTROPHY (ALD)
o Neurodegeneration (Initial apathy and behavioral change, followed by visual loss, spasticity, and ataxia)
o Adrenocortical insufficiency
o Hypogonadism
Where does ketogenesis occur?
liver mitochondria
Substrate for ketogenesis
o Acetyl CoA
* Ketone bodies are alternate fuel sources for tissues like the brain during the fasting phase. They are derived from acetyl CoA. Recall tha acetyl CoA comes from glycolysis when you are well fed, but from beta oxidation when you are fasting.
Products of ketogenesis
o Acetoacetate
o β-hydroxybutyrate
o Acetone
*Of the three ketone bodies, only acetoacetate and β-
hydroxybutyrate can be used as fuel.
rate limiting step of KETOGENESIS
Acetoacetyl CoA + Acetyl CoA → HMG CoA
Enzyme: HMG CoA Synthase
During fasting, there’s almost no glucose available to be converted to acetyl CoA. Free fatty acids in the blood will be sent to the liver to be broken down into acetyl CoA units which can enter ketogenesis. KBs will then be made. KBs are small, can travel to blood & can enter the BBB. As KBs travel in the blood, some KBs can be excreted in the urine &/or one of the KBs (acetone) will be exhaled in the lungs. Once KBs reach the target tissue (extrahepatic), KBs will undergo ketolysis and be converted to AcetylCoA that then enters Krebs cycle (producing 10 ATPs per cycle). Ketogenesis & ketolysis are opposittes but both occur during fasting.
Substrate for Cholesterol Synthesis
Acetyl CoA
The liver is NOT able to use ketone bodies as fuel because it lacks the enzyme ___
succinyl CoA-acetoacetate-CoA transferase (thiophorase)
Describe the structure of cholesterol
o 27-carbon compound
o Steroid nucleus: four fused hydrocarbon rings (A-D)
o An eight-carbon, branched hydrocarbon chain attached to carbon 17 of the D ring
o Hydroxyl group at carbon 3 of the A ring
o Double bond between carbon 5 and 6 of the B ring
Primary bile acids
o Cholic acid
o Chenodeoxycholic acid
Secondary bile acids
o Deoxycholic acid
o Lithocholic acid
• Bile salts
o Conjugated to taurine and glycine (e.g., taurocholic acid, glycocholic acid)
Cholesterol Synthesis
- Acetyl CoA is produced from glucose
- Acetoacetyl-CoA and acetyl-CoA condense to form HMG-CoA
- HMG-CoA is reduced to mevalonate
- Mevalonate is converted to C-5 isoprenoid, isoprenyl pyrophosphate
- Two isoprenyl pyrophosphates condense to form C-10 compound, geranyl pyrophosphate, which reacts with another C-5 compound to form C-15 farnesyl pyrophosphate
- Squalene is formed from two C-15 units, and then oxidized and cyclized to form lanosterol
- Lanosterol is converted to cholesterol
Rate limiting step for Cholesterol Synthesis
Hydroxymethylglutaryl-CoA (HMG CoA) → Mevalonate
Enzyme: HMG-CoA Reductase Requirement: 2 NADPH
are drugs used for the treatment of hypercholesterolemia, to reduce the risk for cardiovascular diseases. They are competitive inhibitors of HMG CoA reductase.
Statins
• 7-dehydrocholesterol reductase deficiency
- Leading to low plasma cholesterol and elevated 7dehydrocholesterol
- Presents with dysmorphic facial features, microcephaly, mental retardation, congenital heart disease, other malformations, often stillborn
SMITH-LEMLI-OPITZ SYNDROME
- Precipitation of cholesterol in the gallbladder
- Results when more cholesterol enters the bile than can be solubilized by the bile salts and phosphatidyl choline present
CHOLELITHIASIS
o Most common form of CAH (>90%)
o Mineralocorticoids and glucocorticoids are absent or deficient
o Overproduction of androgens leads to masculinization of external genitalia in females and early virilization in males
21 -α-Hydroxylase deficiency
- Largest diameter
- Lowest density
• Highest TAG content
Chylomicron
o Decrease in serum cortisol, aldosterone, and corticosterone
o Increased production of deoxycorticosterone causes fluid retention (low-renin hypertension)
o Overproduction of androgens causes masculinization and virilization
11-β1-Hydroxylase Deficiency
- Autoimmune destruction of the adrenal cortex leads to adrenocortical insufficiency
- Acute addisonian crisis precipitated by stress (infection, trauma, surgery, vomiting, diarrhea, or noncompliance with replacement steroids)
- Hyperpigmentation due to excess ACTH stimulating melanocytes to produce melanin
ADDISON DISEASE
Highest cholesterol content
LDL
• Highest protein content
HDL
- Cofactor of lecithin:cholesterol acyltransferase (LCAT)
- Structural component of HDL
Apo A-1
- Mediates assembly and secretion of VLDL
- Structural protein of VLDL, IDL, LDL
Apo B-100
Main apoprotein and mediates secretion of chylomicrons from small intestines
Apo B-48
Cofactor of lipoprotein lipase
Found in Chylomicrons, VLDL IDL, HDL
Apo C-II
Mediates uptake of chylomicron remnants and IDLs
Found in Chylomicron remnants, VLDL, IDL, HDL
Apo E
Type I
Familial Lipoprotein Lipase Deficiency
Type IIa
Familial Hypercholesterolemia
Type III
Familial dysbetalipoproteinemia
Type IV
Familial Hypertriacylglycerolemia
Familial Lipoprotein (a) Excess
Familial hyperalphalipoproteinemia
Abetalipo-proteinemia
Familial alpha-lipoprotein deficiency
Tangier disease
Fish-eye disease
Apo A-1 deficiencies
Metabolism of Chylomicrons
VLDL Metabolism
HDL Metabolism
