9-1 Lipid Biochemistry CIS Flashcards
1
Q
What are the 5 major groups of lipoproteins?
A
Chylomicrons
VLDL
IDL/VLDL remnants
LDL
HDL
2
Q
What are the 4 major types of lipid carried by plasma lipoproteins?
A
Fatty acids
Triglycerides
Cholesterol
Cholesterol esters
3
Q
What are the major types of lipoprotein found in the chylomicron class of lipoproteins?
A
apoB-48
apoC-11
apoE
4
Q
What are the major types of lipoprotein found in the VLDL class of lipoproteins?
A
apoB-100
apoc-11
apoE
5
Q
What are the major types of lipoprotein found in the IDL class of lipoproteins?
A
apoE
apoB-100
6
Q
What is the major type of lipoprotein found in the LDL class of lipoproteins?
A
apoB-100
7
Q
What is the major type of lipoprotein found in the HDL class of lipoproteins?
A
apoA-1
8
Q
How does the liver play a major role in lipid transport and metabolism?
A
Liver takes in glycerol from chylomicron metabolism
also takes in chylomicron remnants from dietary cholesterol
releases FAs on VLDL to adipocytes and mm (from excess glucose or chylomicron remnants)
Picks up IDLs to recycle
Picks up cholesterol from endocytosis of LDL, transfer from HDL
9
Q
How is hepatic VLDL secretion regulated by diet and hormones?
A
VLDL is assembled in hepatocytes to transports triglycerides made from excess glucose
Increased expression of SR-B1 scavenger receptors on steroidogenic tissues to transfer cholesterol into tissue
10
Q
An 18 year old girl was brought to the medical center because of her complaints that she used to get too tired when asked to participate in gym classes. A neurologist found muscle weakness in girl’s arms and legs.
When no obvious diagnosis could be made, biopsies of her muscles were taken for test.
Biochemistry lab results revealed greatly elevated amounts of triglycerides esterified with primary long chain fatty acids.Pathology reported the presence of significant numbers of lipids vacuoles in the muscle biopsy.
What is the cause for these symptoms?
What is the probable diagnosis?
A
carnitine deficiency
Dx: Systemic Primary Carnitine Deficiency
11
Q
FAs (fatty acids) can be used as fuel. What tissue are they liberated from, how are they transported, and where are they consumed?
A
FAs freed from adipocytes
carried in blood on albumin
can be consumed in liver, mm, adipose tissue - almost any cell with mitochondria
12
Q
What is the name of the process where FAs are broken down? What is the end product?
A
beta oxidation –> makes acetyl-CoA
13
Q
What cells/tissues cannot break down FAs? Why?
A
RBCs - breaking down FAs/beta oxidation takes O2, which would be dumb for an RBC to do
Brain/CNS - FAs cannot cross BBB
14
Q
What hormone signals prompts adipocytes to break down fat?
A
decreased insulin
increased epinephrine, cortisol
15
Q
What other molecules are liberated as fuel when fat is broken down in adipocytes?
A
Fat = triglycerides = 3 FAs + glycerol
16
Q
How is glycerol used as fuel?
A
can be made into glucose via DHAP via gluconeogenesis
17
Q
What hormone signals increase gluconeogenesis?
A
increased glucagon and cortisol
18
Q
Why is acetyl-CoA a useful product of beta-oxidation?
A
can make ketone bodies - which mm, brain loves
can also go into TCA cycle
19
Q
What is alpha-oxidation?
A
FAs broken down by removing a single C at the end
20
Q
What is Refsum’s disease?
A
Enzymatic deficiency of alpha-oxidation
Cannot break down dietary phytanic acid and its derivatives
leads to neurological damage
21
Q
What is omega-oxidation?
A
FA oxidation - alternative to beta ocidation, usu for medium-chain FAs
important when beta oxidation is defective
22
Q
What is beta oxidation?
A
FAs are broken down in mitoc to make Ac-CoA, NADH, FADH2
25 enzymes involved, 18 assoc. with human disease/inborn errors of metabolism
23
Q
How do different length FAs get into the mitochondria for oxidation?
A
short and medium chain diffuse in freely
long chain are activated first then transported in via carnitine shuttle
very long chain enter peroxisomes for oxidation
24
Q
What are the relative lengths of short, medium, long and very long chain FAs?
A
short 2-4 C’s
medium 6-12 C’s
long 14-20 C’s
very long >20 C’s
25
How are long chain FAs (LCFAs) activated?
in cytoplasm by ATP and CoA by AcylCoA synthetase
made into fatty acyl CoA
26
How is fatty acyl CoA transported from cytosol into mitoc.?
- Cytosolic Fatty acyl CoA reacts with Carnitine
forming Fatty acyl Carnitine
by **_CAT I_** (carnitine acyl transferase 1) or **_CPT I_** (carnitine palmitoyl transferase I)
Fatty acyl Carnitine
passes to inner mitochondrial membrane, reacts with **_CAT II (CPT II)_**
- Fatty acyl Carnitine
reforms Fatty acyl CoA and enters mitochondrial matrix and b-oxidation
27
Once again, what is the process for transport of LCFAs?
Long chain FAs are activated on outer mitochondrial membrane
Fatty acyl synthetase binds FA + CoA -\> FA-CoA
Carnitine acyltransferase 1 (CAT-1 or CPT I) replaces CoA with carnitine to form FA-carnitine
FA-carnitine translocates across inner mitochondrial membrane by the carnitine transporter
Carnitine releases FA and it is shuttled back across the membrane to transport more FA
Carnitine acyltransferase-2 (CAT-2 or CPT-II) transfers Fatty acyl group back to CoA
vFA-Acyl CoA then undergoes b-oxidation and forms Acetyl CoA
28
What are the signs & sx's of myopathic CAT/CPT deficiency?
mm aches, weakness
myoglobinuria
provoked by prolonged exercise, esp if fasting
biopsy: elevated mm triglyceride
most common form: late-onset
29
What are the signs & sx's of MCAD (medium chain acyl-CoA dehydrogenase deficiency)?
fasting hypoglycemia
no ketone bodies (hypoketosis)
C8-C10 acyl carnitines in blood
vomiting
coma, death
AR with variable expression
30
Carnitine deficiency leads to what and what?
myopathy
encephalopathy
31
What is the pathology behind carnitine deficiency?
leads to impaired carnitine shuttle activity
- decreased LCFA metabolism
- accumulation of LCFAs in tissues and wasting of acyl-carnitine in urine produces:
cardiomyopathy
skeletal muscle myopathy
encephalopathy
impaired liver function
32
What causes carnitine deficiency?
**_Inadequate intake_** (e.g., due to fat diets, lack of access, or long term TPN-total parenteral nutrition)
Inability to metabolize carnitine due to enzyme deficiencies (e.g., CPT deficiency)
Decreased endogenous synthesis of carnitine due to **_severe liver disorder_**
Excess loss of carnitine due to diarrhoea, diuresis, or hemodialysis
A **_hereditary disorder_** in which carnitine leaks from renal tubules (Primary carnitine deficiency)
Increased requirements for carnitine when ketosis is present or demand for fat oxidation is high (e.g., during a critical illness such as sepsis or major burns; after major surgery of the GI tract)
Decreased muscle carnitine levels due to mitochondrial impairment
33
How are CPT-I and II deficiencies treated? (red text)
CPT-I and II treated by avoiding fasting, dietary restrictions of LCFAs, carnitine supplement
34
What is the rate limiting step of FA oxidation? (red text)
carnitine to acyl-carnitine
35
What is the pathogenesis behind carnitine deficiency?
Many diseases have been linked to deficiency of Carnitine, CPT-I and CPT-II
Symptoms range from mild muscle cramping to severe weakness and even death
Muscle, kidney and heart tissues are primarily affected
Muscle weakness during prolonged exercise – important characteristics of CPT deficiency
Muscle relies on FAs as a long term source of energy
Medium chain (C8 - C10) FAs does not require carnitine to enter mitochondria are oxidized normally in these patients
36
What is the timeline for carnitine deficiency?
Most common presentation is progressive cardiomyopathy with or without skeletal muscle weakness beginning at 2-4 years of age.
Energy deprived muscle cells are damaged
Some patients may present with fasting hypoglycemia during the 1st year of life before cardiomyopathy becomes symptomatic.
37
What problems can carnitine/CPT I/CPT II deficiency cause?
* muscle necrosis
* Myoglobinuria
* Rhabdomyolysis
* Hypoglycemia
* fatty liver
* muscle aches
* Fatigue
* cardiomyopathy (age 2-4 yrs, energy deprived muscle cells are damaged)
38
How is carnitine deficiency diagnosed?
Patients have extremely reduced plasma and muscle carnitine levels (1-2% of normal)
Fasting ketogenesis is normal if carnitine transport is normal.
Fasting ketogenesis is impaired when dietary carnitine intake is interrupted.
Hypoglycemia is a common finding.
Hypoglycemia is precipitated by fasting and strenuous exercise.
Muscle biopsy reveals significant lipid vacuoles.
39
What is the treatment for carnitine deficiency?
Pharmacological doses of oral carnitine is highly effective in correcting the cardiomyopathy, muscle weakness, and impairment in fasting ketogenesis
Patient must avoid fasting and strenuous exercise
Some patients require supplementation with medium-chain triglycerides and essential fatty acids (e.g., Linoleic acid, Linolenic acid)
Patients with a fatty acid oxidation disorder require a high-carbohydrate, low fat diet
40
A 24 y/o man complains of “_brown urine_” and _pain in the muscle of his arms and legs_ experienced while playing soccer. The _pain usually resolved overnight_. Physical examination reveals a well-fed male of _normal stature_. A muscle biopsy is taken and sent for specialized testing. Lab findings shows _normal liver enzyme_ _function_. His _cartinine level is also normal_.The patient is sent home with a recommendation to take a dietary carnitine supplement.
Which of the following is the most likely diagnosis?
A. Carnitine deficiency
B. CPT-I deficiency
C. CPT-II deficiency
D. Marfan syndrome
E. MCAD deficiency
CPT-II deficiency
41
What is characteristic of CPT-II deficiency?
mm weakness
brown urine
42
What is characteristic of CPT-I deficiency?
liver dysfxn
43
8 y/o boy suffered gastroenteritis for 3 days that culminate in a brief generalized seizure, which left his comatose. Lab result shows _glucose 45mg/dL (0.25 nM), elevated C8-C10 acyl carnitine levels_, and _no glucose or ketone was detected in his urine. Administering i/v glucose improved his condition within 10 minutes._
Which of the following is the most likely diagnosis?
A. Carnitine deficiency
B. CPT-I deficiency
C. CPT-II deficiency
D. Marfan syndrome
E. MCAD deficiency
MCAD deficiency
44
How can SPCD be summarized?
Systemic primary carnitine deficiency, (SPCD) also known as carnitine uptake defect, carnitine transporter deficiency (CTD) or systemic carnitinedeficiency is an inborn error of fatty acid transport.
Symptoms such as chronic muscle weakness, cardiomyopathy, hypoglycemia and liver dysfunction.
The first suspicion of SPCD in a patient with a non-specific presentation is an extremely low plasma carnitine level
Treatment for SPCD involves high dose carnitine supplementation, which must be continued for life
45
How can CAT-1 deficiency be summarized?
CAT-1 or CPT-I deficiency is a rare metabolic disorder that prevents the body from converting certain fats called long-chain fatty acids into energy, particularly during periods without food.
Symptoms include low levels of ketones and low blood sugar (hypoglycemia).
People with this disorder typically also have an enlarged liver (hepatomegaly), muscle weakness, and elevated levels of carnitine in the blood.
46
How can CPT-II deficiency be summarized?
CAT-2 or CPT-II deficiency is a metabolic disorder characterized by an enzymatic defect that prevents long-chain fatty acids from being transported into the mitochondria for utilization as an energy source.
It is the most common inherited disorder of lipid metabolism affecting the skeletal muscle of adults
Treatment: High-carbohydrate (70%) and low-fat (\<20%) diet to provide fuel for glycolysis; use of carnitine to convert potentially toxic long-chain acyl-CoAs to acylcarnitines
47
What is hyperlipidemia?
Hyperlipidemia or hyperlipoproteinemia is abnormally elevated levels of any or all lipids and/or lipoproteins in the blood
•Hyperlipidemia refers to increased levels of lipids (fats) in the blood, including cholesterol, cholesterol esters (compounds), phospholipids and triglycerides.
48
What determines a lipid particle's impact on metabolism?
The lipoprotein density and type of apolipoproteins it contains determines the fate of the particle and its influence on metabolism
49
What generally causes primary hyperlipidemia? Secondary?
Primary hyperlipidemia is usually due to genetic causes (such as a mutation in a receptor protein), while
Secondary hyperlipidemia arises due to other underlying causes such as diabetes
50
How many different types of primary hyperlipoproteinemia are there? What types should you be familiar with?
5 different phenotypes, with 2 subtypes for type II
know clinical variations of type I and IIa
51
What are the clinical variations or type I primary hyperlipoproteinemia?
Type I hyperlipidemia (familial lipoprotein lipase deficiency)
* Primary disorder
* Deficiency of lipoprotein lipase in tissue leads to hyperlipidemia
* Massive accumulation of **_chylomicrons_** in plasma
* Severe elevation of **_plasma triglyceride_** levels
* Plasma cholesterol levels are not elevated
* **_Manifest in early childhood, with acute pancreatitis_**
* **_Eruptive xanthomas_** - characteristic skin manifestation of this disorder
52
What are the clinical variations of type IIa primary hyperlipoproteinemia?
(i) Type II a
* Accumulation of LDL
* **_Familial LDL receptor deficiency and familial defective apo-B100_**
* Plasma **_cholesterol levels are elevated_**
* Plasma **_triglyceride levels are normal_**
* Manifest **_severe atherosclerosis_**
* May present with:
- **_tendinous xanthomas_**, or
- **_tuberous xanthomas_**, as well as,
- **_xanthelasmas_**
53
What are some causes of secondary hyper-cholesterolemia?
- pregnancy
- hypothyroidism
- cholestasis
- acute intermittent porphyria
54
What are some causes/associations of secondary hyper-triglyceridemia?
- diabetes mellitus
- pancreatitis
- gout
- type I glycogen storage disease
- alcoholism
- oral contraceptive use
55
What are some causes for combined hyper-cholesterolemia and hypertriglyceridemia?
- nephrotic syndrome
- chronic renal failure
- steroid immunosuppressive therapy
56
What cutaneous xanthomas are associated with hyperlipidemia?
5
- xanthelasma palpebrarum
- tuberous xanthomas
- tendinous xanthomas
- eruptive xanthomas
- plane xanthomas
57
What are the characteristics of xanthelasma palpebrarum?
Xanthelasma palpebrarum
- is the most common xanthomas
- lesions are soft, velvety, yellow, flat,
around the eyelids
- associated with hyperlipidemia
- secondary to cholestasis
58
What are the characteristics of tuberous xanthomas?
Tuberous xanthomas
- firm, painless, red-yellow nodules usually develops in pressure areas, extensor surfaces of knees, elbows
- associated with hypercholesterolemia and increased levels of LDL
- secondary to nephrotic syndrome, hypothyroidism
59
What are the characteristics of tendinous xanthomas?
. Tendinous xanthomas
- associated with severe hypercholesterolemia and elevated LDL levels.
- lesions often related to trauma
- nodules related to tendons or ligaments
- secondary to cholestasis
60
What are the characteristics of eruptive xanthomas?
- associated with hyper-triglyceridemia
- erupt as crops of small, red-yellow papules, may spontaneously resolve over weeks
- secondary to diabetes
61
What are the characteristics of plane xanthomas?
Plane xanthomas
- associated with dysbetalipoproteinamia
- can occur in any site
- covers large areas of face, neck, thorax
- secondary to cholestasis
62
What labs would you order for suspected hyper-lipoproteinemia?
Measurement of plasma lipid and lipoprotein levels after an overnight fast of 12-16 hrs.
Abnormal lipoprotein patterns need to be identified.
Performing electrophoresis and ultracentrifugation of whole plasma for diagnosis
Appropriate blood, urine, and radiographic workups are required to rule out secondary causes of hyperlipidemia
Lipoprotein profiles are used to assess cardiac risk and for diagnosis of lipid metabolism disorders
63
Two sisters, aged 17 and 19 years, were referred to the dermatologist because they had large number of yellowish spots on the exposed parts of the body.
On thorough examination and after conducting a series of laboratory investigations they were advised to increase physical activity and reduce the intake of fats.
What is the cause of yellow spots?
yellow spots = xanthomas with hyperlipidemia
64
What are xanthomas? How do they generally develop?
Xanthomas are lesions characterized by accumulation of lipid-laden macrophages
Xanthomas develops in altered systemic lipid metabolism or as a result of local cell dysfunction
Most of the disorders of hyper-lipidemia (hyper-lipoproteinemia)
65
What is the treatment for hyperlipidemia?
Dietary
Lipid-lowering agents, eg. Statins, fibrates, bile acid-binding resins, probucol, or nicotinic acid.
66
What is the treatment and disease course for xanthomas?
- eruptive, tuberous, and tendinous too
Xanthomas are not always associated with hyperlipidemia, but when they are, diagnosing and treatment underlying lipid disorders to decrease the size of xanthomas and to prevent risks of atherosclerosis
Eruptive xanthomas usually resolve within weeks of initiating systemic treatment
Tuberous xanthomas usually resolve after months of treatment
Tendinous xanthomas take years to resolve or may persist indefinitely
67
What is the supportive care and prognosis for hyperlipidemia?
Weight reduction and a diet low in saturated fat and cholesterol are advocated
Patients should avoid alcohol and estrogen
Prognosis – is good if the underlying cause is treated
68
A 45 y/o male presented to the ER with chest pain. The chest pain lasted for approx 15 minutes then subsided on its own. He also noticed that he was nauseated and was sweating during the pain episode. He had no medical problems and had not been to a physician for several years.
On examination, he was in no acute distress with normal vital signs. His lungs were clear to auscultation bilaterally, and his heart had a regular rate and rhythm with no murmurs. An electrocardiogram (ECG) revealed slight ischemic changes. The blood biochemistry revealed **_raised serum total cholesterol and LDL cholesterol levels_**. He was placed on a **_low-fat diet and Lovastatin therapy_**.
He was without complaints and was feeling well on his subsequent follow-up visit. **_On repeat serum cholesterol screening, a decrease in the cholesterol level was noted_**.
What did the patient have?
The patient had an episode of IHD (Ischemic heart disease) and had hyperlipidemia
Hyperlipidemia:
- treatable risk factors of coronary heart disease
- when fasting LDL is found elevated, life style modification, diet, exercise,
weight loss
- if LDL level is still elevated, pharmacological therapy is initiated
69
What is the difference between hyperlipidemia and hypercholesterolemia?
•Hyperlipidemia is caused by an elevated level of any kind of lipid (fat) in the blood stream, while hypercholesterolemia is only caused by high cholesterol in the blood stream.
70
What do hyperlipidemia and hypercholesterolemia cause?
* Although hyperlipidemia and hypercholesterolemia does not cause symptoms, it can significantly increases risk of developing cardiovascular disease, including disease of blood vessels supplying the heart (coronary artery disease), brain (cerebrovascular disease), and limbs (peripheral vascular disease).
* These conditions can in turn lead to chest pain, heart attacks, strokes, and other problems.
* Because of these risks, treatment is often recommended for people with hyperlipidemia.
71
Where does cholesterol come from?
About half the cholesterol of the body arises by synthesis (~700 mg/dL), rest by diet.
All nucleated cells are capable of cholesterol synthesis, which occurs in ER and cytosol.
72
What does HDL do?
HDL is a transporter of cholesterol from peripheral tissues to liver for degradation
73
What does HDL-C do?
HDL-C acts as a scavenger to lower serum cholesterol (good cholesterol)
H = Happy/good cholesterol
74
What does LDL-C do?
LDL-C is a transporter of cholesterol from liver to peripheral tissues
75
What is excess LDL responsible for?
Excess LDL is responsible for artherosclerosis and is a risk factor for IHD (bad cholesterol)
76
What do prolonged elevated levels of VLDL, IDL, or LDL in plasma result in?
Artherosclerosis
– deposition of cholesterol and cholesterol ester from plasma lipoproteins into artery wall
- damage to the endothelium (elevated LDL, free radicals from cigarette smoking, diabetes (glycation of LDL), hypertension (increased advanced glycation end products (AGEs)., etc.
Diabetes mellitus, lipid necrosis, hypothyroidism – often accompanied by severe atherosclerosis, inflammation, free lipid accumulation and necrosis
77
Summarize development of atherosclerosis.
ROS produced by endothelial cells, SMCs, and macrophages oxidize LDL in the subendothelial space, at the sites of endothelial damage, initiating events that culminate in the formation of a fibrous plaque.
Rupture of fibrous plaque leads to thrombus formation and occlusion of the vessel.
78
What are statins?
Statins (Lovastatin, atorvastatin, fluvastatin, pravastatin and simvastatin):
-a family of drugs proved efficacious in lowering plasma cholesterol
79
What is the pharmacology of statins?
act as competitive inhibitors of the enzyme HMG-CoA reductase
- these molecules mimic the structure of the normal substrate of the enzyme (HMG-CoA) and act as transition state analogues
- while statins are bound to the enzyme, HMG-CoA cannot be converted to mevalonate, thus, inhibiting the whole cholesterol biosynthesis process
80
Why are statins so effective? (Hint: why is their target so important?)
HMG-CoA reductase is the rate limiting enzyme.
HMG-CoA reductase inhibitors inhibits de novo cholesterol synthesis and increases LDL receptor expression
81
What is an enzyme in cholesterol synthesis that sounds important, but isn't really?
HMG-CoA synthetase (don't get confused)
82
How do statins work to lower cholesterol?
•Structural analogues of HMG-CoA reductase (rate limiting enzyme in cholesterol synthesis) reduction of cholesterol synthesis in liver
- compensatory increase in synthesis of LDL receptors on hepatic and extra hepatic tissues
- increase in hepatic uptake of circulating LDL which decreases plasma LDL receptors.
* Decrease TGs to some extent and increases HDL
* Cardio protective: vasodilators and decrease atheroscelorosis (stabilize plaque)
83
What are some good effects of statins on a biochemical/cellular level?
cholesterol biosynthesis reduction
reduction of inflammatory molecules and events
improved immunomodulation
antioxidant effect
reduced signaling and gene transcription
reduced cell proliferation
84
What pathological processes can statins help reduce or improve?
atherosclerotic plaque stabilization
reduced platelet aggregation
improved endothelial function
reduced hemorrhagic stress
reduced prothrombotic state
enhanced fibrinolytic state
reduced inflammatory state
85
What diseases are statins protective for?
cardioprotection
stroke protection
anticancer action
improvement of dementia, glaucoma, MS, RA
86
How is hypercholesterolemia treated? Why?
* Reductions in circulating cholesterol levels can have profound positive impacts on cardiovascular disease, particularly on atherosclerosis, as well as other metabolic disruptions of the vasculature.
* Control of dietary intake is one of the easiest and least cost intensive means to achieve reductions in cholesterol.
* Drug treatment to lower plasma lipoproteins and/or cholesterol is primarily aimed at reducing the risk of atherosclerosis and subsequent coronary artery disease that exists in patients with elevated circulating lipids
87
What are some hypolipidemic drugs?
alirocumab (Praluent), evolcumab (Repatha)
atorvastatin (Lipitor), simvastatin (Zoxor), lovastatin (Mevacor)
nicotine acid (Niacor and Niaspan), vitamin B3, niacin
fibrates (Fenofibrate and Gemfibrozil)
ezetimibe: (Zetia or Ezetrol) or with statins (simvastatin/Ezetimibe as Vytorin and Inegy)
bile acid sequestrants (Resins) (Cholestyramine, colestipol and colesevelam)
88
How do fibrates work?
- activators of the peroxisome proliferator-activated receptor-α (PPARα) class of proteins that are classified as nuclear receptor co-activators.
- In the liver this leads to increased β-oxidation of fatty acids, thereby decreasing the liver's secretion of triacylglycerol- and cholesterol-rich VLDLs, as well as increased clearance of chylomicron remnants, increased levels of HDLs and increased lipoprotein lipase activity which in turn promotes rapid VLDL turnover
89
