LIPID METABOLISM

PROGRAM KBK
FK-UKI

Prof. Dr. drh. Maria Bintang, MS

GURU BESAR BIOKIMIA

REFERENCES

Lehninger. 2000. Principles of biochemistry 3rd Ed.

Michael W. King. 2006. Medical Biochemistry.
Murray R K, Granner D k, Mayers P a & Rodwell V w.
2003. Harpers Illustrated Biochemistry. 26th Ed.
Pratt,C.W.and Cornely K. 2004. Essential
Biochemistry. Wiley International Edition.
Stryer, Lubert 1995. Biochemistry.4th Ed.
Sung Hee Um. 2004. The Role of S6K1 in
Development and Maintenance of Nutrient
Homeostasis.[dessertation]. Basel.

Lipids
Lipids include oils, fatty acids, waxes, steroids

(such as cholesterol and estrogen), and other related

compounds.
The functions of lipids are:
Fats (lipids) are an important source of energy
for the body, as ATP.
Lipids are fat-like substances that are important
parts of the membranes found within and
between each cell
In the myelin sheath that coats and protects the
nerves.

Adipocytes at the crossroads of energy homeostasis

Adipose tissue, which is the

main energy storage site, is
responsive to both central and
peripheral metabolic signals by
regulating lipid storage and
mobilization.
Dietary fat is absorbed through
the gastrointestinal tract in the
form of circulating
chylomicrons and very-lowdensity lipoprotein (VLDL),
part of which is metabolized to
provide energy and the rest of
which enters the liver and
adipose tissues for short- and
long-term storage, respectively.

As a gauge of the level of energy reserves, adipose tissues secrete

several adipokines, such as leptin, which regulates energy
homeostasis by signalling to the brain and peripheral tissues.
Adipose tissues, through the lipolysis and re-esterification process,
are also the main sites for fatty-acid cycling, thereby securing the
energy supply to oxidative tissues, such as skeletal muscle and the
heart. The liver has an important role as a homeostat for transient
energy fluctuation; it protects other tissues from
POSTPRANDIAL TRIGLYCERIDAEMIA by temporarily storing
FAs from the circulation as a benign derivative, triacylglycerol
(TAG), and secreting them as VLDL when the period of
maximum lipid load has passed.
The liver is also an important site for energy conversion,
exchanging energy sources from one form to another, such as
glycogen to glucose, fatty acid to TAG and saturated fatty acid to
unsaturated fatty acid. CNS, central nervous system.

The process of dietary lipid digestion and absorption

triacylglycerol (TAG)
FA-transport protein-4 (FATP4).
bile salts (BS)
cholesterol (CL)
FA-transport protein-4 (FATP4).
acyl-CoA:cholesterol acyltransferase (ACAT)
chylomicrons (CM)

phospholipids (PLs)
Fatty acid transferase (FAT=CD36)
lysophosphatidic acid (LPA)
intestinal FA-binding protein (IFABP)
glycerol-3-phosphate acyltransferase (GPAT)
cholesterol esters (CE).
microsomal triglyceride transfer protein (MTP),

A. Dietary lipid digestion begins in the stomach.

Where lipids are subjected to partial digestion by gastric lipase
and form large fat globules with hydrophobic triacylglycerol
(TAG) cores surrounded by polar molecules, including
phospholipids (PLs), cholesterol (CL), fatty acids (FAs) and
ionized proteins.
The digestive processes are completed in the intestinal lumen,
where large emulsions of fat globules are mixed with bile salts
(BS) and pancreatic juice containing lipid digestive enzymes to
form an aqueous suspension of small fatty droplets to maximize
exposure to the pancreatic lipases for lipid hydrolysis.
Monoacylglycerol (MAG), diacylglycerol (DAG) and free FAs
that are released by lipid hydrolysis join BS, CL,
lysophosphatidic acid (LPA) and fat-soluble vitamins to form
mixed micelles that provide a continuous source of digested
dietary products for absorption at the brush-border membranes
of the enterocytes.

B. FAs and MAG enter the enterocytes by passive diffusion and are
facilitated by transporters, such as intestinal FA-binding protein
(IFABP), CD36 and FA-transport protein-4 (FATP4).
They are then re-esterified sequentially inside the
endoplasmic reticulum by MAG acyltransferase (MGAT) and
diacylglycerol acyltransferase (DGAT) to form TAG.
Phospholipids from the diet as well as bile - mainly LPA - are
acylated by 1-acyl-glycerol-3-phosphate acyltransferase
(AGPAT) to form phosphatidic acid (PA), which is also
converted into TAG.
Dietary CL is acylated by acyl-CoA:cholesterol
acyltransferase (ACAT) to cholesterol esters (CE).
Facilitated by microsomal triglyceride transfer protein (MTP),
TAG joins CE and apolipoprotein B (ApoB) to form
chylomicrons (CM) that enter circulation through the lymph

Lipid storage and mobilization in adipocytes

lipoprotein lipase (LPL)

glycerol-3-phosphate acyltransferase (GPAT)
1-acylglycerol-3-phosphate acyltransferase (AGPAT)
free fatty acids (FFAs)
phosphatidic-acid phosphohydrolase (PAP)
perilipin (PER)
phosphate acyltransferase (PAT)
protein kinase A (PKA)

acyl-CoA synthase (ACS)

MAG acyltransferase (MGAT).
diacylglycerol acyltransferase (DGAT).
lipoprotein lipase (LPL)
adipose differentiation-related protein (ADRP)
tail-interacting protein of 47 kDa (TIP47)
hormone-sensitive lipase (HSL).
lysophosphatidic acid (LPA)

The main metabolic functions of adipose tissue are the accumulation of

surplus energy through triacylglycerol (TAG) synthesis and deposition
(lipogenesis), and lipid mobilization by releasing free fatty acids (FFAs)
under conditions of negative energy balance (lipolysis).

FFAs that are released from lipoprotein chylomicrons and very-lowdensity lipoprotein (VLDL) catalysed by lipoprotein lipase (LPL)
enters the adipocytes through both passive diffusion and active
transport. Intracellular FFA is first converted to acyl-CoA by acyl-CoA
synthase (ACS), and is then used as a substrate by two parallel TAGsynthetic pathways in the (ER).

Glycerol-3-phosphate (G3P) that is generated by glucose metabolism is

acylated sequentially by glycerol-3-phosphate acyltransferase (GPAT)
and sn-1-acylglycerol-3-phosphate acyltransferase (AGPAT), and
converted to diacylglycerol (DAG) by phosphatidic-acid
phosphohydrolase (PAP); by contrast, the alternative pathway involves
the acylation of monoacylglycerol (MAG) by MAG acyltransferase
(MGAT). The two pathways merge with the acylation of DAG to TAG
by diacylglycerol acyltransferase (DGAT).

Nascent lipid droplets that are generated from the ER are coated
by at least one of the PAT family proteins (which includes
perilipin (PER), adipose differentiation-related protein (ADRP)
and tail-interacting protein of 47 kDa (TIP47)) and S3-12,
whereas mature lipid drops are mainly coated with perilipin.
The mechanism by which other PAT proteins are replaced with
perilipin is unclear. The relative rate of lipogenesis and lipolysis
is determined by nutritional states and is regulated by endocrine
factors, such as catecholamines and insulin, which impose their
effect by the phosphorylation of perilipin and hormonesensitive lipase (HSL).
The phosphorylation of perilipin allows HSL to access lipid
droplets, which results in the hydrolysis of TAG to FFAs that
are then released from the adipocytes. PA, phosphatidic acid;
PKA, protein kinase A; LPA, lysophosphatidic acid.

Interconnection of metabolic pathways involved in lipid synthesis in the endoplasmic

reticulum and lipid oxidation in mitochondria of liver and skeletal muscle

carnitine palmitoyl transferase (CPT)

acyl-carrier protein (ACP)
malonyl-CoA decarboxylase (MCD)
acetyl-CoA carboxylase (ACC)

Stearoyl-CoA desaturase-1 (SCD1)

acyl-CoA synthase (ACS)
phosphatidylglycerophosphate synthase (PGPS)
fatty-acid synthase (FAS )

 Among the lipid metabolic enzymes, acetyl-CoA

carboxylase (ACC), fatty-acid synthase (FAS) and

carnitine palmitoyl transferase (CPT) are the three main
enzymes that regulate the synthesis of malonyl-CoA,
which is the principal inhibitor of fatty-acid entry into
mitochondria for -oxidation. Stearoyl-CoA desaturase-1
(SCD1) regulates lipid oxidation by converting stearic
acid (18:0) to oleic acid (18:1).
The saturated fatty acyl-CoAs are known to
allosterically inhibit ACC1, whereas monounsaturated
fatty acyl-CoAs are the preferred substrates for the lipid
synthesis of triacylglycerol (TAG) in the endoplasmic
reticulum (ER).
Malonyl-CoA and stearic acid reciprocally regulate the
entry of acyl-CoA into mitochondria by modulating the
activity of CPT.

Lysophosphatidic acid (LPA) and phosphatidic acid (PA) are

synthesized in the ER; they are also produced in mitochondria
and transported to the ER where the terminal enzymes for
TAG synthesis are located.
Mitochondrial FAS (FAS II) and acyl-carrier protein (ACP)
are involved in fatty-acid synthesis, but their role in lipid
metabolism remains elusive.
ACS, acyl-CoA synthase; AGPAT, acylglycerol-3-phosphate
acyltransferase; CLS, cardiolipin (CL) synthase; DGAT,
diacylglycerol (DAG) acyltransferase; GPAT, glycerol-3phosphate (G-3-P) acyltransferase; MCD, malonyl-CoA
decarboxylase; MGAT, monoacylglycerol (MAG)
acyltransferase; PAP, phosphatidic-acid phosphohydrolase;
PGPS, phosphatidylglycerophosphate (PGP) synthase; TAG,
triacylglycerol; TCA, tricarboxylic-acid cycle.

Pathways of lipid absorption and pooling within the enterocyte

monoglyceride (MG)

glycerol-3 phosphate (G3P)

chylomicron (CM)

smooth endoplasmic reticulum (SER)

rough endoplasmic reticulum (RER)

lipoproteins (LPs)

Following uptake across the apical membrane of the enterocyte,

the products of gastrointestinal (GI) lumen lipid digestion
monoglyceride (MG) and fatty acid (FA) can either diffuse
across the enterocyte and enter the portal vein blood or be resynthesized to triglyceride (TG) by either the 2-monoglyceride
(2-MG) pathway associated with the smooth endoplasmic
reticulum (SER) or the a-glycerol-3 phosphate (G3P) pathway
associated with the rough endoplasmic reticulum (RER).
TG formed by these pathways typically enters the ER lumen and
is assembled into lipoproteins (LPs; represented by orange
circles).
LPs are then transported to the Golgi, exocytosed from the
enterocyte and taken up into the intestinal lymphatic system.
As lipid contained within the lipoprotein assembly pathways and
the Golgi is destined for transport to the systemic circulation by
the intestinal lymphatic system, this pool of lipids is referred to
as the lymph lipid precursor pool.

A cytosolic pool of lipids is also located within the enterocyte.

This lipid pool comprises excess TG formed by the G3P pathway
and endogenous lipids taken up from the intestinal blood supply
in the form of either FA or chylomicron (CM) remnants.
The cytosolic lipids are subject to hydrolysis by cytosolic lipase
and the digestion products formed can be re-circulated into TG
assembly pathways. However, the majority of lipids from this
pool exit the enterocyte in the form of TG or free FA and are
taken up into portal vein blood.
The pool of lipids that is transported from the enterocyte by the
portal vein is therefore referred to as the portal lipid precursor
pool (dashed red line).
Recent evidence suggests that the trafficking and pooling of
lipids within the enterocyte have a significant influence on the
intracellular disposition of lipophilic drugs

Enzymes and functions found to be

activated by PPAR/ peroxisome
proliferator-activated receptor
(PPAR) agonist are marked in
green.
Red indicates inhibition of pathways.
The green arrows underline FA
uptake and oxidation, followed
by uncoupling oxidation from ATP
synthesis.

Schematic of Metabolic PPAR/ Action

ABC
ADRP
ACS
PDK
UCP
FABP

: ATP-binding cassette transporter

: adipose differentiation-related protein
: acyl-CoA synthase
: phosphoinositide-dependent protein kinase
: uncoupling protein
: Fatty acid binding protein

GLUT
SCD
CPT
PDC
GYG1
MUFAs

: Glucose transporter
: Stearoyl-CoA desaturase
: carnitine palmitoyl transferase
: pyruvate dehydrogenase complex
: glycogenin 1
: monounsaturated fatty acid

The sequence of events postulated to occur during the development of

dietinduced obesity and metabolic syndrome
Note:
SREBP-1c: Sterol regulatory element binding protein-1c, also known as
adipocyte determination and differentiation factor-1, ADD-1

Pathway for the movement of acetyl-CoA units from within the

mitochondrion to the cytoplasm for use in lipid and cholesterol biosynthesis

cytosol

mitokondria

Lehninger. 2000

CHOLESTEROL

Cholesterol is an extremely important biological

molecule that has roles in membrane structure as
well as being a precursor for the synthesis of the
steroid hormones and bile acids. Both dietary
cholesterol and that synthesized de novo are
transported through the circulation in
lipoprotein particle

The synthesis and utilization of cholesterol must

be tightly regulated in order to prevent overaccumulation and abnormal deposition within the
body. Of particular importance clinically is the
abnormal deposition of cholesterol and
cholesterol-rich lipoproteins in the coronary
arteries. Such deposition, eventually leading to
atherosclerosis, is the leading contributory factor
in diseases of the coronary arteries.

Biosynthesis of
Cholesterol

Regulating Cholesterol
Synthesis

Regulation of HMGR by covalent modification. HMGR

(Hydroxymethylglutaryl CoA reduktase) is most active in the
dephosphorylated state.
Phosphorylation is catalyzed by AMP-activated protein kinase,
AMPK, (used to be termed HMG kinase), an enzyme whose activity
is also regulated by phosphorylation.
Phosphorylation of AMPK is catalyzed by AMPK kinase (AMPKK).
Hormones such as glucagon and epinephrine negatively affect
cholesterol biosynthesis by increasing the activity of the inhibitor of
phosphoprotein phosphatase inhibitor-1, PPI-1.
Conversely, insulin stimulates the removal of phosphates and,
thereby, activates HMGR activity.
Additional regulation of HMGR occurs through an inhibition of its'
activity as well as of its' synthesis by elevation in intracellular
cholesterol levels.
This latter phenomenon involves the transcription factor SREBP
(sterol regulatory element binding proteins) described below.

Bile Acids Synthesis and Utilization

The end products of cholesterol utilization are the bile acids,
synthesized in the liver. Synthesis of bile acids is one of the
predominant mechanisms for the excretion of excess cholesterol.
However, the excretion of cholesterol in the form of bile acids is
insufficient to compensate for an excess dietary intake of cholesterol.
Bile acids perform four physiologically significant functions:
1. Their synthesis and subsequent excretion in the feces represent the
only significant mechanism for the elimination of excess
cholesterol.
2. Bile acids and phospholipids solubilize cholesterol in the bile,
thereby preventing the precipitation of cholesterol in the
gallbladder.
3. They facilitate the digestion of dietary triacylglycerols by acting as
emulsifying agents that render fats accessible to pancreatic lipases.
4. They facilitate the intestinal absorption of fat-soluble vitamins.

Lipoprotein

A lipoprotein is a biochemical assembly that contains both

proteins and lipids. The lipids or their derivatives may be
covalently or non-covalently bound to the proteins.
Many enzymes, transporters, structural proteins, antigens,
adhesins and toxins are lipoproteins. Examples include the
high density and low density lipoproteins of the blood, the
transmembrane proteins of the mitochondrion and the
chloroplast, and bacterial lipoproteins
Lipoproteins in the blood, carry fats around the body. The
protein particles have charged groups aimed outward so as to
attract water molecules; this makes them soluble in the salt
water based blood pool.

Triglyceride-fats and cholesterol are carried internally,

shielded by the protein particle from the water.
The interaction of the proteins forming the surface of the
particles with (a) enzymes in the blood, (b) with each other
and (c) with specific proteins on the surfaces of cells
determine
Triglycerides and cholesterol will be added to or removed
from the lipoprotein transport particles.

Classification of Lipoprotein

General categories of lipoproteins, listed in order from larger

and less dense (more fat than protein) to smaller and more dense
(more protein, less fat):
A. Chylomicrons - carry triacylgycerol (fat) from the
intestines to the liver and to adipose tissue .
B. Very low density lipoproteins - carry (newly synthesised)
triacylglycerol from the liver to adipose tissue.
C. Intermediete density lipoproteins - are intermediate between
VLDL and LDL. They are not usually detectable in the
blood.
D. Low density lipoproteins - carry cholesterol from the liver to
cells of the body. Sometimes referred to as the "bad
cholesterol" lipoprotein.
E. High density lipoproteins - collects cholesterol from the
body's tissues, and brings it back to the liver. Sometimes
referred to as the "good cholesterol" lipoprotein

A.

Low-density lipoprotein (LDL)

Its size is approx. 22 nm. Each native LDL particle contains

a single apolipoprotein B-100 molecule (Apo B-100, a
protein with 4536 amino acid residues) that circles the fatty
acids keeping them soluble in the aqueous environmen
Generally, LDL transports cholesterol and triglycerides
from the liver
Because LDLs transport cholesterol to the arteries and can
be retained there by arterial proteoglycans starting the
formation of plaques, increased levels are associated with
atherosclerosis, and thus heart attack, stroke and peripheral
vascular disease. This is why cholesterol inside LDL
lipoproteins is called bad cholesterol.

 High

concentrations of small LDL particles correlates with

much faster growth of atheroma, progression of
atherosclerosis and earlier and more severe cardiovascular
disease events and death.
LDL is formed as VLDL lipoproteins lose triglyceride
through the action of lipoprotein lipase (LPL) and become
smaller and denser, containing a higher proportion of
cholesterol.
A hereditary form of high LDL is familial
hypercholesterolemia (FH). Increased LDL is termed
hyperlipoproteinemia type II with symptom abdominal pain,
enlarged liver, enlarged spleen, increased blood cholesterol,
and LDL

LDL import

to the cell

When a cell requires cholesterol, it synthesises the

necessary LDL receptors, and inserts them into the
plasma membrane. The LDL receptors diffuse freely
until they associate with clathrin coated pits. LDL
particles in the blood stream bind to these extracellular
LDL receptors. The clathrin coated pits then form
vesicles which are endocytosed into the cell.
After the clathrin coat is shed the vesicles deliver the
LDL and their receptors to early endosomes, onto late
endosomes to lysosomes. Here the cholesterol esters in
the LDL are hydrolysed. The LDL receptors are
recycled back to the plasma membrane

 Recommended range; changing targets . The

American Heart Association , provide a set of guidelines for

fasting LDL-Cholesterol levels, estimated or measured, and
risk for heart disease. As of 2003, these guidelines were:

Level (mg/dL)

Level mmol/L

Interpretation

< 100

< 2.6

100 to 129

2.6 to 3.3

Near optimal LDL level

130 to 159

3.3 to 4.1

Borderlinehigh LDL level

160 to 189

4.1 to 4.9

High LDL level

> 190Very

> 4.9

Optimal LDL cholesterol, corresponding to

reduced, but not zero, risk for heart disease

High LDL level, corresponding to highest

increased risk of heart disease

B. High density lipoprotein

Their size (811 nm in diameter), that carry cholesterol

from the body's tissues to the liver. About thirty percent of

blood cholesterol is carried by HDL.
It is hypothesised that HDL can remove cholesterol from
atheroma within arteries and transport it back to the liver
for excretion or re-utilizationwhich is the main reason
why HDL-bound cholesterol is sometimes called "good
cholesterol", or HDL-C. A high level of HDL-C seems to
protect against cardiovascular diseases, and low HDL
cholesterol levels (less than 40 mg/dL) increase the risk for
heart disease.
When measuring cholesterol, any contained in HDL
particles is considered as protection to the body's
cardiovascular health.

Recommended range. The American Heart Association,

provides a set of guidelines for male fasting HDL levels and
risk for heart disease.
Level mg/dL

Level mmol/L

<40

< 1.03

4059

1.031.52

>60 disease

>1.55

Interpretation
Low HDL cholesterol, heightened
risk for heart disease, < 50 is the
value for women
Medium HDL level
High HDL level, optimal condition
considered protective against heart

Obesity

Obesity is a condition in which the natural energy reserve,

stored in the fatty tissue of humans and other mammals, is
increased to a point where it is associated with certain health
conditions or increased mortality.
Although obesity is an individual clinical condition, it is
increasingly viewed as a serious and growing public health
problem: excessive body weight has been shown to predispose
to various diseases, particularly cardiovascular diseases,
diabetes mellitus type 2, sleep apnea, and osteoarthritis
BMI, or body mass index, is a simple and widely used method
for estimating body fat. In epidemiology BMI alone is used as
an indicator of prevalence and incidence.

 BMI was developed by the Belgian statistician and

anthropometrist Adoplhe Quetelet.It is calculated by

dividing the subject's weight by the square of his/her
height, typically expressed either in metric or US
Customary units:
Metric: BMI = kg / m
Where kg is the subject's weight in Kg and m
is the subject's height in metres.
US/Customary: BMI = lb * 703 / in
Where lb is the subject's weight in pounds and
in is the subject's height in inches.

The current definitions commonly in use establish the following

values, agreed in 1997 and published in 2000:
2000

BMI less than 18.5 is underweight

BMI of 18.524.9 is normal weight
BMI of 25.029.9 is overweight
BMI of 30.039.9 is obese
BMI of 40.0 or higher is severely (or morbidly) obese
BMI of 35.0 or higher in the presence of at least one
other significant comorbidity is also
classified by some odies as morbid obesity

A large number of medical conditions have been associated

with obesity:
Cardiovascular, congestive

heart failure, enlarged heart

and its associated arrhythmias and dizziness, cor
pulmonale, varicose veins, and pulmonary embolisme
Endocrine: polycystic ovarian syndrome (PCOS),
menstrual disorders, and infertility
Gastrointestinal : gastroesophageal reflux disease (GERD),
fatty liver disease, cholelithiasis (gallstones), hernia, and
colorectal cancer
Renal and genitourinary : erectile dysfunction, urinary
incontinence, chronic renal failure, hypogonadism (male),
breast cancer (female), uterine cancer (female), stillbirth
Integument (skin and appendages): stretch marks,
acanthosis nigricans, lymphedema, cellulitis, carbuncles,
intertrigo

 Musculoskeletal:

hyperuricemia (which predisposes to gout),

immobility, osteoarthritis, low back pain
Neurologic: stroke, meralgia paresthetica, headache, carpal
tunnel syndrome, dementia
Respiratory : dyspnea, obstructive sleep apnea,
hypoventilation syndrome, Pickwickian syndrome, asthma
Psycholoical : depression, low self esteem, body dysmorphic
disorder, social stigmatization
Causes and mechanisms
Lifestyle (excessive nutrient intake)
Genetics (genes controlling appetite, metabolism, and
adipokine release predispose to obesity)
Medical illness (hypothyroidism, Cushingsyndrome,
growth hormone deficiency)
Social determinants (fast food)

Therapy, In a clinical practice guideline by the

American College of Physicians, the following five
recommendations are mad:

People with a BMI of over 30 should be counseled on diet,

exercise and other relevant behavioral interventions, and set
a realistic goal for weight loss.
If these goals are not achieved, pharmacotherapy can be
offered. The patient needs to be informed of the possibility
of side-effects and the unavailability of long-term safety and
efficacy data.
Drug therapy may consist of sibutramine, orlistat,
phentermine, diethylpropion, fluoxetine, and bupropion. For
more severe cases of obesity, stronger drugs such as
amphetamine and methamphetamine may be used on a
selective basis. Evidence is not sufficient to recommend
sertraline, topiramate, or zonisamide.

 In patients with BMI

> 40 who fail to achieve their weight

loss goals (with or without medication) and who develop
obesity-related complications, referral for bariatric surgery
may be indicated. The patient needs to be aware of the
potential complications.
Those requiring bariatric surgery should be referred to
high-volume referral centers, as the evidence suggests that
surgeons who frequently perform these procedures have
fewer complications.

Lipid storage disorder

The body's store of fat is constantly broken down and
reassembled to balance the body's energy needs with the food
available.
Groups of specific enzymes help the body break down and
process fats. Certain abnormalities in these enzymes can lead
to the buildup of specific fatty substances that normally would
have been broken down by the enzymes.
Over time, accumulations of these substances can be harmful
to many organs of the body.
Disorders caused by the accumulation of lipids are called
lipidosis. Other enzyme abnormalities result in the body being
unable to properly convert fats into energy. These
abnormalities are called fatty acid oxidation disorders

Lipid storage disorders (or lipidoses) are a group of inherited

metabolic disorders in which harmful amounts of lipids (fats)
accumulate in some of the bodys cells and tissues.
Types Lipid storage disorders
Gauser disease
Niemann-Pick disease
Fabry disease
Farbers disease
Gangliosidoses = Tay-Sachs disease
Krabb disease
Metachromatic leukodystrophy
Wolmans disease

Gaucher disease
Gaucher disease is the most common of the lipid storage
diseases.
It is caused by a deficiency of the enzyme
glucocerebrosidase.
Fatty material can collect in the spleen, liver, kidneys, lungs,
brain, and bone marrow.
Gaucher disease has three common clinical subtypes:
o

Type 1 (or nonneuropathic type) is the most common form of the

disease. It occurs most often among persons of Ashkenazi Jewish
heritage. Symptoms may begin early in life or in adulthood and
include enlarged liver and grossly enlarged spleen, which can rupture
and cause additional complications. Skeletal weakness and bone
disease may be extensive. The brain is not affected, but there may be
lung and, rarely, kidney impairment. Patients in this group usually
bruise easily and experience fatigue due to low blood platelets

Type 2 (or acute infantile neuropathic Gaucher disease) typically

begins within 3 months of birth. Symptoms include an enlarged
liver and spleen, extensive and progressive brain damage, eye
movement disorders, spasticity, seizures, limb rigidity, and a poor
ability to suck and swallow. Affected children usually die by age 2
platelets
Type 3 (the chronic neuronopathic form) can begin at any time in
childhood or even in adulthood. It is characterized by slowly
progressive but milder neurologic symptoms compared to the acute
or type 2 version. Major symptoms include an enlarged spleen
and/or liver, seizures, poor coordination, skeletal irregularities, eye
movement disorders, blood disorders including anemia and
respiratory problems. Patients often live to their early teen years
and often into adulthood.

For type 1 and most type 3 patients, enzyme replacement

treatment given intravenously every two weeks can
dramatically decrease liver and spleen size, reduce skeletal
abnormalities, and reverse other manifestations.

Niemann-Pick disease
Niemann-Pick disease is actually a group of autosomal
recessive disorders caused by an accumulation of fat and
cholesterol in cells of the liver, spleen, bone marrow,
lungs, and, in some patients, brain, because of
sphingomyelinase deficiency.
Neurological complications may include ataxia,eye
paralysis, brain degeneration, learning problems,
spasticity, feeding and swallowing difficulties, slurred
speech, loss of muscle tone, hypersensitivity to touch, and
some corneal clouding.
A characteristic cherry-red halo develops around the center
of the retina in 50 % of patients.

Niemann-Pick disease is currently subdivided into four

categories:
o

Onset of type A, the most severe form, is in early infancy. Infants

appear normal at birth but develop an enlarged liver and spleen,
swollen lymph nodes, nodes under the skin (xanthemas), and
profound brain damage by 6 months of age. The spleen may enlarge
to as much as 10 times its normal size and can rupture. These
children become progressively weaker, lose motor function, may
become anemic, and are susceptible to recurring infection. They
rarely live beyond 18 months. This form of the disease occurs most
often in Jewish families
type B (or juvenile onset), enlargement of the liver and spleen
characteristically occurs in the pre-teen years. Most patients also
develop ataxia, peripheral neuropathy, and pulmonary difficulties that
progress with age, but the brain is generally not affected. Type B
patients may live a comparatively long time but many require
supplemental oxygen because of lung involvement

Niemann-Pick disease types C and D are not caused by a

deficiency of sphlingomyelinase but by a lack of the NPC1 or
NPC2 proteins. As a result, various lipids and cholesterol
accumulate inside nerve cells and cause them to malfunction.
Patients with types C and D have only moderate enlargement of
their spleens and livers. Brain involvement may be extensive,
leading to inability to look up and down, difficulty in walking and
swallowing, and progressive loss of vision and hearing.
Type D patients typically develop neurologic symptoms later than
those with type C and have a progressively slower rate of loss of
nerve function. Most type D patients share a common ancestral
background in Nova Scotia. The life expectancies of patients with
types C and D vary considerably. Some patients die in childhood
while others who appear to be less severely affected live into
adulthood.

Fabry disease

Fabry disease, also known as alpha-galactosidase-A deficiency, causes a

buildup of fatty material in the autonomic nervous system, eyes, kidneys,
and cardiovascular system
Fabry disease is the only x-linked lipid storage disease. Males are
primarily affected although a milder form is common in females, some of
whom may have severe manifestations similar to those seen in affected
males.
Fatty storage in blood vessel walls may impair circulation, putting the
patient at risk for stroke or heart attack. Other symptoms include heart
enlargement, progressive kidney impairment leading to renal failure,
gastrointestinal difficulties, decreased sweating, and fever.
Angiokeratomas (small, non-cancerous, reddish-purple elevated spots on
the skin) may develop on the lower part of the trunk of the body and
become more numerous with age
Patients with Fabry disease often die prematurely of complications from
heart disease, renal failure, or stroke. Drugs such as phenytoin and
carbamazepine are often prescribed to treat pain that accompanies Fabry
disease

Farbers disease

Farbers disease, also known as Farbers lipogranulomatosis or

ceramidase deficiency, describes a group of rare autosomal recessive
disorders that cause an accumulation of fatty material in the joints,
tissues, and central nervous system
The disorder affects both males and females. Disease onset is typically
in early infancy but may occur later in life. Children who have the
classic form of Farbers disease develop neurological symptoms within
the first few weeks of life. These symptoms may include moderately
impaired mental ability and problems with swallowing. The liver, heart,
and kidneys may also be affected.
Other symptoms may include vomiting, arthritis, swollen lymph nodes,
swollen joints, joint contractures (chronic shortening of muscles or
tendons around joints), hoarseness, and xanthemas which thicken
around joints as the disease progresses. Patients with breathing
difficulty may require insertion of a breathing tube. Most children with
the disease die by age 2, usually from lung disease. In one of the most
severe forms of the disease, an enlarged liver and spleen
(hepatosplenomegaly) can be diagnosed soon after birth. Children born
with this form of the disease usually die within 6 months.

Krabb disease
Krabb disease (also known as globoid cell leukodystrophy and
galactosylceramide lipidosis) is an autosomal recessive disorder
caused by deficiency of the enzyme galactosylceramidase.
The disease most often affects infants, with onset before age 6
months, but can occur in adolescence or adulthood. The buildup of
undigested fats affects the growth of the nerves protective myelin
sheath and causes severe degeneration of mental and motor skills.
Other symptoms include muscle weakness, hypertonia (reduced
ability of a muscle to stretch), myoclonic seizures (sudden, shocklike contractions of the limbs), spasticity, irritability, unexplained
fever, deafness, optic atrophy and blindness, paralysis, and
difficulty when swallowing. Prolonged weight loss may also occur.
The disease may be diagnosed by its characteristic grouping of
certain cells, nerve demyelination and degeneration, and destruction
of brain cells. In infants, the disease is generally fatal before age 2.
Patients with a later onset form of the disease have a milder course
of the disease and live significantly longer.

Metachromatic leukodystrophy
Metachromatic leukodystrophy, or MLD, is a group of disorders
marked by storage buildup in the white matter of the central
nervous system and in the peripheral nerves and to some extent in
the kidneys
Similar to Krabb disease, MLD affects the myelin that covers
and protects the nerves. This autosomal recessive disorder is
caused by a deficiency of the enzyme arylsufatase A. Both males
and females are affected by this disorder.
The most common form of the disease is late infantile, with onset
typically between 12 and 20 months following birth. Infants may
appear normal at first but develop difficulty in walking and a
tendency to fall, followed by intermittent pain in the arms and
legs, progressive loss of vision leading to blindness,
developmental delays, impaired swallowing, convulsions, and
dementia before age 2.
Death generally occurs within 6 to 14 years after onset of
symptoms.

Wolmans disease
Wolmans disease, also known as acid lipase deficiency, is
a severe lipid storage disease that is usually fatal by age 1.
This autosomal recessive disorder is marked by
accumulation of cholesteryl esters (normally a transport
form of cholesterol) and triglycerides (a chemical form in
which fats exist in the body) that can build up significantly
and cause damage in the cells and tissues
Both males and females are affected by this severe
disorder. Infants are normal and active at birth but quickly
develop progressive mental deterioration, enlarged liver
and grossly enlarged spleen, distended abdomen,
gastrointestinal problems including steatorrhea (excessive
amounts of fats in the stools), jaundice, anemia, vomiting,
and calcium deposits in the adrenal glands, causing them to
harden.

Gangliosidoses = Tay-Sachs disease

Tay-Sachs disease (abbreviated TSD, also known as
GM2 Gene map locus. Hexosaminidase A deficiency
or Sphingolipidosis) is a genetic disorder, fatal in its
most common variant known as Infantile Tay-Sachs
disease. TSD is inherited in an autosomal recessive
pattern. The disease occurs when harmful quantities of a
fatty acid derivative called a ganglioside accumulate in
the nerve cells of the brain. Gangliosides are lipids,
components of cellular membranes, and the ganglioside
GM2, implicated in Tay-Sachs disease, is especially
common in the nervous tissue of the brain.

Tay-Sachs disease is a rare disease. Other

autosomal disorders such as cystic fibrosis and sickle
cell anemia are far more common. The importance of
Tay-Sachs lies in the fact that an inexpensive enzyme
assay test was discovered and subsequently
automated, providing one of the first "mass
screening" tools in medical genetics.
Gangliosides are lipids, components of cellular
membranes, and the ganglioside GM2, implicated in
Tay-Sachs disease, is especially common in the
nervous tissue of the brain.