Transcript M01

Advanced Nutrition
Lipids metabolism
MargiAnne Isaia, MD MPH
LIPIDS
LIPID OXIDATION:
Cellular transport of fatty acids uses Carnitine shuttle
Beta oxidation of fatty acids is a complete oxidation.
The end result of this oxidation is Acetyl CoA.
Well fed state :
Fasting, starvation,
exercise:
- fatty acids come from diet
- fatty acids come from storage (adipose)
If SCTG consumed : more energy production
(direct transfer, more rapid oxidation)
LCFA n-3 and n-6 more rapidly oxidized than SFA
SCTG short chain triglycerides
LIPIDS
MOBILIZATION OF FFAs
1. Fasting, starvation, exercise
-Glucagon and Epinephrine are released
-these hormones stimulate Hormone-Sensitive Lipase (HSL)
HSL breaks down TAG to FFA and glycerol
2. FFAs bound to albumin
transported to metabolizing tissue
Glycerol transported to the liver for gluconeogenesis.
FFAs- activated to FFA acylCoA – taken up by mitochondria to be
oxidized
LIPIDS
LIPIDS
CARNITINE SHUTTLE
Carnitine is synthesized from Lysine (LYS) and Methionine (MET)
SCFA, MCFA do not use carnitine shuttle.
Carnitine and three enzymes: CPT I and II, CAT are involved in the transfer
Carnitine deficiency- impaired oxidation of FAs- diseases associated with
hyperglycemia.
Carnitine deficiency: -primary (systemic) genetic origin, developed from mutation of
carnitine transporter OCTN2
(progressive cardiomyopathy skeletal myopathy,
hypoglycemia, hyperammoniemia)
- secondary to many genetic / acquired disorders
(episodic hypoketotic hypoglycemia, starting in infancy)
Carnitine supplementation :
supposed to increase energy production,
because it facilitates the FA transport into mitochondria for oxidation,
sparing glycogen from the muscles during exercise;
could mitigate lactate production
Studies: carnitine is not a ergogenic aid to increase sport performance.
LIPIDS
b OXIDATION
Oxidation of FAs result in removal of AcetylCoA (2 carbon)
molecule at a time
12C fatty acid will produce 6 AcetylCoA molecules
Energetics of FA oxidation
even chain FA – end product Acetyl CoA – enters TCA cycle
odd chain FA – 3 C residue remains (Propionyl CoA)
Propionyl CoA is the only part of FA that is glucogenic.
B vitamin, Biotin = coenzyme for Propionyl CoA carboxylase
Vitamin B12 = coenzyme for Methylmalonyl CoA isomerase.
MMA = Methylmalonic Acid – byproduct of Methylmalonyl CoA.
hMMA + hHomocysteine level = Vitamin B 12 deficiency
h Homcysteine level + normal MMA= folate deficiency
LIPIDS
TYPE OF FFAs AND OXIDATION
Effects of FFAs with greater retention
- predispose to obesity
- alter membrane fluidity (receptor-ligand)
- influence eicosanoid metabolism
SCFAs, MCFAs faster oxidation
- direct absorption
- do not require chylomicrons for transport
- do not use Carnitine shuttle for oxidation
PUFAs faster oxidation than SFA
- faster mobilization from adipose
preferred substrate for HSL
- hepatic FA oxidation
bypasses first step in oxidation
(+) oxidative enzymes (induction)
- mitochondrial entry
preferred uptake for by Carnitine shuttle
LIPIDS
PEROXISOMAL OXIDATION
- primarily for VLCFA (>20 C)
-a modified form of b oxidation
- first dehydrogenation reaction uses FAD
-Hydrogen is not transferred to ETC, but to molecular O2, forming H202
-This is disposed by catalse
Purpose is to fragment VLCFA prior to b oxidation
Then b oxidation
2 coenzymes: NAD & FAD
NAD/NADH g 3ATP
FAD/FADH g 2 ATP
LIPIDS
LIPID PEROXIDATION
Lipids g oxidized by Reactive Oxygen Species
(ROS: superoxide, OH-, singlet oxygen, HOCL)
Oxidative stress
g circumstances that increase oxidant exposure
result in increased formation of ROS
(chemicals, drugs, decreased antioxidant capability)
Free radicals (ROS) look for H in the body
Lipids are high in hydrogen atoms
Unsaturated lipids – more H atoms unstable
(C=C highly unstable, FA becomes more reactive)
Free radicals damage FFA, DNA, proteins
Phases in formation of free radicals: initiation, propagation,
termination
ROS balanced with anti-oxidants in healthy people.
LIPIDS
LIPID PEROXIDATION
Lipid peroxidation (partial oxidation) occurs with PUFA
End products are aldehydes and hydrocarbon gases
- TBARS, MDA are markers of lipid peroxidation:
useful in research :
TBARS in blood, urine, after fish oil administration
Membrane integrity affected
- permeability increases
- receptor–ligand interaction decreases
- enzyme activity decreases.
TBARS = THIOBARBITURIC ACID REACTIVE SUBSTANCE
MDA = MALON DIALDEHYDE
LIPIDS
LIPID PEROXIDATION
Vitamin E – terminator of peroxidation
(chain-breaking antioxidant because it donates a hydrogen atom
for lipid radicals)
Glutathione peroxidase - effective in reducing lipid peroxides (selenoperoxidases)
PUFA/Vitamin E ratio indicates peroxidative capacity
- Vegetable oilsg good PUFA/Vitamin E ratio
- Fish oilg high PUFA, low vitamin E
PUFA and vitamin E must be together
Important: limit PUFA intake
(<10% of total energy from PUFA)
LIPIDS
FA BIOSYNTHESIS
SFA synthesized in the cytoplasm
Enzyme: Fatty Acid Synthetase complex
Site: liver (primarily), adipose (minor)
Acethyl CoA--building block
Rate limiting enzyme is Acethyl CoA carboxylase
- fat free diet: (+) enzyme (induction = up-regulation)
- high PUFA diet: (-) enzyme (repression = down-regulation)
Acetyl CoA (2C) ggggg palmitic acid (16C)
(enzyme complex)
LIPIDS
FA BIOSYNTHESIS
End product is Palmitic Acid ( C16:0)
Used for energy/storage
Chain elongation and desaturation can occur
Location: ER membranes
Desaturase D9, D6, D5, D4 ( enzymes specific for double bond
position)
Elongase helps in synthesis of VLCFA (brain, nervous system)
EFFECTS OF DESATURASE AND ELONGASE ON ESSENTIAL FATTY ACIDS
n-7 EFA
n-9 EFA
n-6 EFA
n-3 EFA
Palmitic
16:0
Stearic
18:0
Palmitoleic
16:1 n-7
Oleic
18:1 n-9
Linoleic
18:2 n-6
a- linoleic
18:3 n-3
18:2 n-9
g- Linolenic
18:3 n-6
18:4 n-3
18:2 n-7
20:2 n-9
Dihomo- g linolenic
20:3 n-6
20:4 n-3
18:3 n-7
Eicosatrienoic
20:3 n-9
Arachidonic
20:4 n-6
Eicosapentaenoic
20:5 n-3
22:3 n-9
Docosatetraenoic
22:4 n-6
22:5 n-3
22:5 n-6
Docosahexaenoic
22:6 n-3
D9 desaturase
D6 desaturase
16:2 n-7
elongase
D5 desaturase
elongase
20:3 n-7
D4 desaturase
LIPIDS
DESATURASE PATHWAY
18:2 n-6 (Linoleic Acid) and 18:3 n-3 (a-Linolenic Acid)
n-3 and n-6 cannot interconvert
affinity for desaturases: n-3 > n-6 > n-9
For the same quantity of substrate available first will be used n-3
from n-3 FA will result n-3FA
from n-6 FA will result n-6 FA
EFA:
For Unsaturated FA- desaturases are common
Eicosatrienoic acid C20:3 n-9 – maker to asses Essential Fatty
Acids ( n-9 EFA not physiologically important)
Arachidonic acid (C20:4 n-6) pro-inflammatory effect
EPA ( C 20:5 n-3) – anti-inflammatory effect
DHA ( C 20:6 n-3) – anti-inflammatory effect
Arachidonic acid must be balanced with EPA/DHA
LIPIDS
DESATURASE PATHWAY
- excess of n-6 FA will reduce n-3 FA metabolism
- nutritional implications
-18:1 n-9 level needs to be very high to compete with n-6 and n-3
In EFA deficiency C18:1 n-9 converted to 20:3 n-9
(eicosatrienoic acid = biomaker for EFA status)
During hydrogenation positional isomers of FA are formed (Trans FA)
Trans FA compete with EFA and SFA for desaturase and elongase
Diet impacts desaturase enzymes
LIPIDS
DESATURASE PATHWAY
Diet impacts desaturase enzymes activity
(American diet – too much n-6 FA
Enzymes will convert Linoleic Acid to Arachidonic Acid)
D6 desaturase- increased activity:
- fat-free diet
- protein and EFA deficiency
- Insulin
D6 desaturase- decreased activity:
- alcohol
- Glucagon, Epinephrine, NE, Thyroxine,
Glucocorticoids, Diabetes
(catabolic states)
LIPIDS
CHOLESTEROL SYNTHESIS
Liver g site for endogenous synthesis of Cholesterol
Acetyl CoA precursor
HMG CoA reductase is rate limiting enzyme:
(3 Hydroxy-3 Methyl-Glutaryl Coenzyma A reductase))
Body regulates the Cholesterol synthesis:
- feedback (-) (h cholesterol – inhibits the enzyme activity)
- hormonal: Insulin (+)
- via Sterol Regulatory Element Binding Protein (SREBP)
down-regulates enzyme expression
STATIN Drugs – competitive inhibitor of HMG–CoA Reductase
- decrease Cholesterol synthesis
- interfere with other pathway (CoQ10)
CoQ10 (ubiquitin) involved in energy metabolism
Statin drugs side effects i CoQ10, extreme fatigue
Maybe: take CoQ10 as supplement, if under Statin drugs.
LIPIDS
REFERENCES
1. Shils M et al, Modern Nutrition in Health and Disease, 10th Edition
2. www. Pubmed.org
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