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Lipid metabolism
Lipids:
Are heterogeneous group of compounds related to the fatty acids. Lipids are biological
molecules that are insoluble in aqueous solutions and soluble in organic solvents (ether,
chloroform, and benzene), therefore, physical properties reflect the hydrophobic nature
of their structures.
Lipid functions:
1.They serve as structural components of biological membranes (controls the flow of
materials in and out of the cell (barrier).
2.They provide energy reserves, predominantly in the form of triacylglycerols.
3. Both lipids and lipid derivatives serve as hormones.
4.Interactions with vitamins, assist in the regulation of biological processes.
5.Lipophilic bile acids aid in lipid solubilization.
Classification of lipids:
1.Simple lipids: is ester of fatty acids(F.A) with alcohol include:
-Fats: ester of fatty acids with tri hydroxic alcohol (glycerol).
- Ester of F.A.( saturated ) with glycerol called fats (solid).
- Ester of F.A.( unsaturated ) with glycerol called oils (liquid).
2.Waxes: ester of F.A. with higher molecular weight monohydric alcohol (e.g.: insect
secretions)
3.Complex lipids : ester of fatty acid -containing groups in addition to fatty acid and
alcohol , include: a.Phospholipids: b.Glycolipid: c.Other complex lipids like sulfolipids,
aminolipids, and lipoproteins d. Precursor and derived lipids : these include fatty acids ,
glycerol , ketone bodies, cholesterol and glycerides.
Blood lipids
Blood lipids (or blood fats) are lipids in the blood, either free or bound to other molecules.
They are mostly transported in a protein capsule, the concentration of blood lipids depends
on intake and excretion from the intestine, and uptake and secretion from cells. Blood
lipids are mainly fatty acids and cholesterol. Hyperlipidemia is the presence of elevated or
abnormal levels of lipids and/or lipoproteins in the blood, and is a major risk factor for
cardiovascular disease. A blood test called a complete lipid profile is done. It is
recommended that this test be done after an overnight fast. An excess amount of blood
lipids can cause fat deposits in the artery walls, increasing the risk for heart disease.
Healthy lipid levels
1- total cholesterol should be less than 200
2- HDL cholesterol should be 40 or higher
3- LDL cholesterol should be less than 100.
4- triglyceride level should be less than 150
If the lipids are not at the right levels, what can be done to improve them?
1- follow a diet low in saturated fats and cholesterol.
2- In some cases,it may also need to take a medication to help lower the lipid levels.
Body stores of fat
Fats and Energy: Protein, carbohydrates and fats are the three essential nutrients that
provide the body with caloric energy. Fats are the most energy dense of these nutrients.
Containing 9 kcal per gram, fats provide roughly twice as much energy and calories as
proteins and carbohydrates which only provide 4 kcal per gram. This energy is used for
exercising and for basic biological processes, known as the basal metabolic rate, that the
body performs while at rest. These include functions like blood circulation, the regulation
of hormones, cell growth and digestion. Any calories that are not immediately metabolized
for energy are stored in the body as fat for future use.
Adipocytes:
Fat is stored throughout the body in fat cells known as adipocytes. However, fat cells can
increase and decrease in size depending on the amount of fat that the body is storing. If the
body stores more fat then it uses, the fat cells will expand causing weight gain. If the body
is forced to rely on stored fat reserves for energy, whether because of diet or exercise, the
fat cells will shrink causing weight loss.
Fatty acids
1- Are aliphatic carboxylic acids mostly obtained from the hydrolysis of natural fats and
oils.
2- Fatty acids that occur in natural fats usually contain an even number of carbon atoms,
because they are synthesized from 2 carbon units and are straight-chain derivatives. The
chain may be saturated (containing no double bonds), or unsaturated (containing one or
more double bonds).
3- At physiological pH, the carboxyl group is readily ionized, rendering a negative charge
onto fatty acids in bodily fluids, therefore F.A. are weak acids.
a- Monounsaturated …(one double bond),
b- Polyunsaturated .(2 or more of double bonds ).The most important of polyunsaturated
fatty acids are the Essential Fatty Acids(EFAs). The EFAs are those fatty acids that are
required in human body but cannot be synthesized in it, so must be supplied in the diet to
support the growth and include:
Linoleic acid C18, 2 double bonds
Linolenic acid C18, 3 double bonds
Arachidonic acid C20, 4 double bonds
The absolute EFAs are the linoleic acid, the precursor of arachidonic acid that is a
substrate for Prostaglandins synthesis and the Linolenic acid, the precursor for other ω-3
fatty acids formula important for growth and development. These EFAs are important
components of phospholipids of cell membrane and mitochondrial membrane.
Eicosanoids
Extremely powerful hormone like molecules but are not hormones rather autocrine
linoleic acid
regulators. Derived from arachidonic acid which is synthesized from
linoleic acid by adding a two carbon unit and additional double bonds, there are three types
of ecosanoids:
•Prostaglandins: (pain, fever, ovulation, uterine contraction, gastric secretion inhibition)
•Thromboxanes: possess a cyclic ether in their structures; TxA2 is the most prominent
member of this group and is primarily produced by platelet (clotting).
•Leukotrines: are cause fluid leakage from blood vessels to inflamed
area.
Triglyceride; TG (Triacylglycerol):Are fatty acid ester of glycerol alcohol; 3 fatty acids+
Glycerol. Diglyceride; 2 fatty acids+ Glycerol. Monoglycride: 1 fatty acid+ Glycerol.
TG represents (its function) the principal storage form of energy in adipose tissues that
needed physiologically in prolonged fasting and starvation and pathologically, for example
in uncontrolled diabetes mellitus. Triglycerides undergo lipolysis (hydrolysis by lipases)
and are broken down into glycerol and FA. Once released into the blood, FFA bind to
serum albumin for transport to tissues that require energy. The glycerol also enters the
bloodstream and is absorbed by the liver or kidney where it is converted to glycerol 3phosphate by the enzyme glycerol kinase. Hepatic glycerol 3-phosphate is mostly
converted into dihydroxyacetone (DHAP) and then glyceraldehyde 3-phosphate to rejoin
the glycolysis and gluconeogenesis pathway.
Properties of F.A.:
fatty acids are weak acids and dissociate in solution as RCOOH ↔ RCOO‾ + H‾ .
Boiling points and melting points of fatty acids rise with increase of chain length.
In general, saturated F.A. of more than 10 C-atoms are solids at room temperature,
In unsaturated F.A. the melting point is greatly lowered and solubility in non-polar
solvents is enhanced with increase the number of double bonds.
Phospholipids
These lipids also composed of Fatty acids(R) and Glycerol as TG, but also phosphoric
acid(PO4) and nitrogen base. These two latter structures(PO4 and nitrogen base) confer the
PL compounds the relative polarity and so their function in CM and mitochondrial
membrane structures.
PLs are also reffered to as amphipathic compounds because of their formation from
polar(PO4 and nitrogen base) and nonpolar(fatty acids) structures.
Sphingolipids
These are also PL but differ from phosphoglycerolipids in their structure: They are
composed of Sphingosine alcohol instead of Glycerol.
Sphingosine+fatty acid=Ceramide
Ceramide+Nitrogen base= sphingolipid.
Of the most significant type of these PL in humans is sphingomyelin in which the base is
choline. It is an important component of myelin sheath of nerve fibers, insulates and
protects neuronal fibers of the central nervous system.
Glycolipids: Ceramide+ carbohydrate moity(or moities)=Glycolipids. Of which : the
simple forms are glucosylsphingolipid and galactosylsphingolipid(only one unit of CHO).
The complex forms are Globoside and Gangalioside(2-9 units of CHO).
Cholesterol : Is anthor form of lipid called sterols. Cholesterol is the major sterol in
humans. It is cycloaliphatic carbon chain C27. It is present in blood in two forms: Free
chol.(1/3) and Esterified chol.(2/3). Total chol. Represents the two forms: The free form is
relatively polar because of free OH group at C3, while the esterified form is nonpolar
because the free OH is occupied by acyl group(fatty acid RCOO) .
Cholesterol is the precursor for synthesis of many vital substances: Male and Female sex
hormones (Androgen such as testosterone and Estrogen, E2 ), vitamin D, Cortisol and
aldosterone hormones.
Cholesterol synthesis:
Sources of cholesterol:
1- Dietary intake: Most cells derive their cholesterol from LDL or HDL.
2- De novo synthesis: Occurs in the liver, where cholesterol is synthesized from acetylCoA in cytoplasm.
The sequential steps of formation of cholesterol
1- AcetylCoA (2 C): Citrate shuttle shifts mitochondrial Acetyl-CoA into cytoplasm.
2- AcetoacetylCoA (4 C): Action of 3-Hydroxy-3-MethylGlutaryl (HMG) – CoA synthase
(cytoplas).
3- HMG CoA (6 C):
a- Action of HMG-CoA reductase (rate-limiting enzyme of the mevalonate pathway, the
metabolic pathway that produces cholesterol and other isoprenoids.
b- Inhibited by: Statins, Glucagon, Cholesterol.
c- Activated by: Insulin.
4- Mevalonate (6 C): Pyrophyosphorylation.
5- Pyrophosphomevalonate (6 C): Decarboxylation.
6- Dimethylallyl Isopentanyl pyrophosphate (5 C): Isomerization
7- Dimethylallyl pyrophosphate (5 C): Addition of isopentanyl pyrophosphate (5 C).
8- Geranyl pyrophosphate (10 C): Addition of isopentanyl pyrophosphate (5C).
9- Farnesyl pyrophosphate (15 C)
A- Action of Squalene synthase (2 X Franesyl pyrophosphate ).
B- NADPH required.
C- Franesyl PPi is important for:
a- Synthesis of CoQ (Electron Transport Chain).
b- Synthesis of Dolichol PPi for N-linked glycosylation of proteins.
c- Prenylation of proteins (post-translational modification).
10- Squalene (30 C):
a- Action of Squalene epoxidase.
b- NADPH required
11- Lanosterol (30 C):
Series of 19 reactions
12- Cholesterol (27 C):
a- Component of cell membrane.
b- Steroid synthesis.
c- Vitamin D synthesis.
d- Bile acid synthesis.
β-oxidation of Fatty Acids: Fatty acid β-oxidation is a multistep process by which
fatty acids are broken down by various tissues to produce energy. Fatty acid β-oxidation is
major metabolic pathway that is responsible for the mitochondrial breakdown of long-chain
acyl-CoA to acetyl-CoA in the cytosol in prokaryotes and in the mitochondria in
eukaryotes. Acetyl-CoA enters the citric acid cycle, and NADH and FADH2, which are
co-enzymes used in the electron transport chain. It is named as such because the beta
carbon of the fatty acid undergoes oxidation to a carbonyl group. It requires a set of
enzymes. The oxidation is so called because the β carbon is oxidized during the oxidation
process.
Steps of Beta-Oxidation: The enzyme, acyl-CoA ligase, uses adenosine triphosphate,
or ATP, to join a fatty acid with CoA. They form a new molecule called acyl-CoA. It is as
acyl-CoA that the fatty acids are able to broken down in the mitochondrial matrix.
There are four main steps—or acts—in beta-oxidation:
1- Loss of hydrogens
2- Addition of water
3- Loss of another hydrogen
4- Addition of another CoA
Figure 1. Fatty Acid Oxidation Overview
Phospholipid Biosynthesis:
Phospholipids are a class of lipids that consist of two fatty acyl molecules esterified at the
sn-1 and sn-2 positions of glycerol, and contain a head group linked by a phosphate residue
at the sn-3 position.
Figure 1. Structure and major classes of phospholipids
Figure 2. Phospholipid biosynthesis
Abbreviations: GPAT, glycerol 3-phosphate acyltransferase; AGPAT, acylglycerol-3acyltransferase; PAP, phosphatidic acid phosphatase; CDS, CDP-diacylglycerol synthase;
PA, phosphatidic acid; DAG, diacylglycerol; PC, phosphatidylcholine; PE,
phosphatidylethanolamine; TAG, triacylglycerol; PI, phosphatidylinositol; PG,
phosphatidylglycerol.
ketosis and ketone body formation:
Ketosis is a metabolic state in which some of the body's energy supply comes from ketone
bodies in the blood. Ketosis is a nutritional process characterised by serum concentrations
of ketone bodies over 0.5 mM, with low and stable levels of insulin and blood glucose. It is
almost always generalized with hyperketonemia, that is, an elevated level of ketone bodies
in the blood throughout the body. Ketone bodies are formed by ketogenesis when liver
glycogen stores are depleted (or from metabolising medium-chain triglycerides).
The main ketone bodies used for energy are acetoacetate and β-hydroxybutyrate, and the
levels of ketone bodies are regulated mainly by insulin and glucagon. Most cells in the
body can use both glucose and ketone bodies for fuel, and during ketosis, free fatty acids
and glucose synthesis (gluconeogenesis) fuel the remainder. In glycolysis, higher levels of
insulin promote storage of body fat and block release of fat from adipose tissues, while in
ketosis, fat reserves are readily released and consumed. For this reason, ketosis is
sometimes referred to as the body's "fat burning" mode.While ketosis and ketoacidosis are
frequently confused with one another, they are certainly not the same. Ketoacidosis is an
acute life-threatening condition requiring prompt medical intervention. However, there are
situations (such as treatment-resistant epilepsy) where ketosis can be rather beneficial to
health.
Ketone bodies:
Ketone bodies are three water-soluble molecules (acetoacetate, beta-hydroxybutyrate, and
their spontaneous breakdown product, acetone) that are produced by the liver from fatty
acids during periods of low food intake (fasting), carbohydrate restrictive diets, starvation,
prolonged intense exercise, or in untreated (or inadequately treated) type 1 diabetes
mellitus. These ketone bodies are readily picked up by the extra-hepatic tissues, and
converted into acetyl-CoA which then enters the citric acid cycle and is oxidized in the
mitochondria for energy. In the brain, ketone bodies are also used to make acetyl-CoA into
long-chain fatty acids.
Ketone bodies are produced by the liver under the circumstances listed above (i.e. fasting,
starving, low carbohydrate diets, prolonged exercise and untreated type 1 diabetes mellitus)
as a result of intense gluconeogenesis, which is the production of glucose from noncarbohydrate sources (not including fatty acids). They are therefore always released into
the blood by the liver together with newly produced glucose, after the liver glycogen stores
have been depleted. (These glycogen stores are depleted after only 24 hours of fasting).
When two acetyl-CoA molecules lose their -CoAs, (or Co-enzyme A groups) they can form
a (covalent) dimer called acetoacetate. Beta-hydroxybutyrate is a reduced form of
acetoacetate, in which the ketone group is converted into an alcohol (or hydroxyl) group
(see illustration on the right). Both are 4-carbon molecules, that can readily be converted
back into acetyl-CoA by most tissues of the body, with the notable exception of the liver.
Acetone is the decarboxylated form of acetoacetate which cannot be converted back into
acetyl-CoA except via detoxification in the liver where it is converted into lactic acid,
which can, in turn, be oxidized into pyruvic acid, and only then into acetyl-CoA.
Ketone bodies have a characteristic smell, which can easily be detected in the breath of
persons in ketosis and ketoacidosis. It is often described as fruity or like nail polish
remover (which usually contains acetone or ethyl acetate).
Apart from the three endogenous ketone bodies, acetone, acetoacetic acid, and betahydroxybutyric acid,[4] other ketone bodies like beta-ketopentanoate and betahydroxypentanoate may be created as a result of the metabolism of synthetic triglycerides,
such as triheptanoin.
Ketone Bodies
When the level of acetyl CoA from β-oxidation increases in excess of that required for
entry into the citric acid cycle, It undergoes ketogenesis in the mitochondria of liver
(ketone body synthesis). The three compounds: acetoacetate, β-hydroxybutyrate, and
acetone are collectively known as ketone bodies.
Causes of Ketosis:
1.Prolonged starvation, depletion of carbohydrate stores results in increased fatty acid
oxidation and ketosis.
2.Lactating mothers develop ketosis, if the carbohydrate demands are not met with.
3.Diabetic patients with uncontrolled blood glucose,
Lipoproteins:
Lipoproteins LPs are spherical structures composed from lipids and. In these structures
the water insoluble lipids (TG and esterified cholesterol) are oriented to the core of the
spherical LP, while the water soluble lipids(PL, Free chol. and added proteins) are directed
to the surface of LP. However, these structures in their later form still relatively insoluble
in systemic circulation and need for addition of specific proteins, called apolipoproteins to
confer them sufficient water solubility and so transporting in blood.
Chylomicron(Exogeneous LP):
It is synthesized in small intestine from dietary lipid after being digested and absorbed.
Chylomicron composed mainly of TG 90 %, and the remainder are PLs, cholesterol and
apoLPs. Because of its low density(large size), Chylomicrons - carry triacylglycerol (fat)
from the intestines to the liver and to adipose tissue(exogenous triglyceride).
VLDL (Endogeneous pathway):
VLDL is also composed mainly of TG but with less amount compared with chylomicron
(VLDL contains 55-60 % TG). It contains also apo B100, much amount of PL , cholesterol
and apoproteins, so with higher density and smaller size than chylomicron.VLDL
synthesized endogeneously in the liver from chylomicron remnant(dietary lipid)?? and
from those synthesized in the liver from excess ingested CHO??.
VLDL - carry (newly synthesised or endogenous) triacylglycerol from the liver to adipose
tissue.
Intermediate density lipoprotein IDL
Hydrolysis of TG by LPL to produce what is known: IDL. This IDL which is present
normally in blood transiently, is composed from equal molar amount of cholesterol and
TG, and mainly apo B100 and apo E. IDL - are intermediate between VLDL and LDL.
LDL Low Density Lipoprotein:
This type of lipid or LP is differentiated from other LPs in its principally forming from
cholesterol(free and esterified) and only apo B 100. LDL - carry cholesterol from the liver
to cells of the body. Sometimes referred to as the "bad cholesterol" lipoprotein.[LDL] .
because of direct correlation between the blood levels of this lipid and the incidence of
atherosclerosis; coronary artery diseases(CADs), cerebrovascular disease(CVD), and the
peripheral atherosclerosis.
HDL High Density Lipoprotein:
It is synthesized in the liver and small intestine as disk-shapped containing only PL and apo
A II(the predominant apoLP),C and E. HDL - collects cholesterol from the body's tissues,
and brings it back to the liver. The inverse relation between the plasma HDL-C and the
incidence of CAD (and in general atherosclerosis) made it the Good lipid or LP.
Apolipoproteins(apos):
Apolipoproteins are protein components of lipoproteins. They have three main functions:
a.As structural components, which help stabilize a polar lipids in plasma.
b.Apos bind to cell surface receptors, thus determining the sites of cellular uptake and
degradation of lipoproteins.
c.Apos regulate the activity of enzymes which are involved in lipoprotein metabolism.
After digestion of lipids, some changes are happened in intestine for absorption, these are:
•Hydrolysis of triglycerides(TG) to free fatty acids(FFA) and mono- acylglycerols.
• Solubilization of FFA and monoacylglycerols by detergents (bile acids) and
transportation from the intestinal lumen toward the cell surface.
• Uptake of FFA and monoacylglycerols into the cell and resynthesis to triglycerides.
• Packaging of newly synthesized TG into special lipid- rich globules called chylomicrons.
• Exocytosis of chylomicrons from cells and release into lymph.
Hyperlipidemia hyperlipoproteinemia or dyslipidemia: is the presence of raised
or abnormal levels of lipids and/or lipoproteins in the blood. Lipid and lipoprotein
abnormalities are extremely common in the general population, and are regarded as a
highly modifiable risk factor for cardiovascular disease ,atherosclerosis. ,acute pancreatitis.
Hypercholesterolemia: is the presence of high levels of cholesterol in the blood. It is not a
disease but a metabolic derangement that can be secondary to many diseases and can
contribute to many forms of disease, most notably cardiovascular disease. It is closely
related to the terms.
Familial hypercholesterolemia is a rare genetic disorder that can occur in families,
where sufferers cannot properly metabolise cholesterol.
Hypocholesterolemia: Abnormally low levels of cholesterol, some studies suggest a
link with depression, cancer and cerebral hemorrhage.
Metabolic Response to Starvation
Energy Reserves
1- Liver/muscle glycogen: are sufficient for brief period (<24hr) of fasting –
mostly used for emergencies (vigorous exercise).
a- Liver can release glucose into blood via Glucose-6-Pase; Muscle must
consume its own glycogen
2- Muscle protein: is another possible source but is unfavorable since you would in
effect digest your muscles
3- Adipose TG’s: provide the major storage form of readily-available energy –
provides FFA’s to liver which makes ketones that are necessary for prolonged
starvation.
4- Fuel homeostasis: principally regulates the needs of brain and muscle
(major consumers of fuel).
a- brain – glucose exclusively (120g/d) until prolonged starvation (~2 days)
then switches to ketones (fuel sparing).
Metabolic Changes during Starvation
Mechanisms of Protein Conservation
A- Muscle protein breakdown during starvation provides liver (for gluconeogenesis) and
kidney (for ammoniagenesis).
B- During 1st days of starvation, amino acids (Ala, Gln) are synthesized and released from
muscle
- Ala goes to liver for gluconeogenesis
- Gln goes to kidney for ammoniagenesis (also yields glucose); or goes to gut and
converted to Ala which goes to liver
C- As starvation progresses, ammoniagenesis required to maintain acid-base homeostasis
rises in kidney (due to increased FFA’s and circulating ketones) which secondarily yields
more glucose thus kidney becomes major source of gluconeogen.
- By 3 days starvation, brain begins utilizing ketones and skeletal muscle relies on ketones
for 50% of its energy.
- The switch from glucose to ketone usage aids in reducing the rate of muscle protein
degradation needed for gluconeogenesis – if this did not occur, the body would lose >½ of
its muscle protein within 17 days leading to death.
- By 24 days starvation, ketone synthesis, nitrogen excretion, and gluconeogen (from
lactate, glycerol, Gln) reach a steady state allowing starvation to persist for 2 – 3 months.
Ketone Body Metabolism
1- Increased availability of FFA’s during starvation provides liver with increased levels
of acetyl CoA and eventually exceeds the oxidative capacity of the liver, thus acetyl CoA is
shifted from the TCA cycle towards ketone synthesis.
2- Acetyl CoA is made into HMG-CoA via HMG-CoA Synthase (rate-limiting enzyme –
only found in liver); HMG-CoA is then made into acetoacetate, b-hydroxybutyrate, and
acetone (minor) and released into blood since liver cannot utilize them. Ketones are used
by skeletal and cardiac muscle, the renal cortex, and other tissues (brain only uses during
starvation).
3- Role of the Kidney
a- Kidney, like liver, possesses the complete enzymatic apparatus for gluconeogenesis
b- During brief periods of starvation, kidney’s rate of gluconeogenesis is 10% to that of the
liver
c- During prolonged starvation, ammoniagenesis increases due to increased acid load
which accelerates its rate of gluconeo
d- The principle gluconeogenic substrate is Gln which also provides the free NH3 (used to
titrate excess H+ ions).
4- Hormonal Control During Starvation
a- Insulin levels decrease (aids FA mobilization, gluconeogenesis and ketone production)
b- Growth hormone increases (stimulates lypolysis) with a reduction in thyroid hormone
(major energy conserving adaptation by decreasing basal metabolic rate and limiting
muscle protein breakdown0
c- Glucagon (stimulates gluconeogenesis) Ý , then returns to postabsorptive levels
concurrent with reduced glucose demand.