Study Guide Block Nutrition

Samy S. Ramadan NMGI Study Guide – Block 2 of 89

AMINO ACID METABOLISM II

Describe the two main pathways of protein degradation in eukaryotic cells and understand the conditions under which they are employed.

Pathway 1 – The Lysosomal Protein Degradation System Lysosomes are membrane encapsulated, acidic organelles that contain hydrolytic enzymes.

o Contain proteases and hydrolases and have a low pH (4.8-5).o They are not a major pathway for normal turnover of proteins.

Lysosomes degraded proteins non-selectively in well-nourished cells. There are 2 Methods of Entering the Lysosomal Pathway.

o Endocytosis : Extracellular material and plasma membrane are enclosed into endosomes/vacuoles that fuse with lysosomes.

o Cytosolic Encapsulation: Cytosolic proteins are encapsulated in autophagic vacuoles that fuse with lysosomes; normally maintains the balance of cellular components, but a major “triage” mechanism in starving cells.

The LPDS is not involved in selective protein degradation under normal conditions. Selective protein degradation is activated after a prolonged fast.

o Proteins with specific AA sequences are degraded by lysosomes.o Results in selective loss of proteins from tissues that atrophy in response to fasting (Liver

and Kidney), but nor from tissues that do not atrophy (Brain and Testes). Diabetes mellitus; Muscle Wastage from Disuse; Denervation; Regression of Uterus after birth.

Pathway 2 – The Ubiquitin/Proteasome System The Ubiquitin-Proteasome Proteolytic Pathway is a specialized set of cytoplasmic proteins which

can delete incorrectly assembled proteins and direct them to sites for proteolysis.

ACTIVATION

CONJUGATION

LIGATION


E1, E2, & E3 With each step there is an increasing level of regulatory specificity. Number of enzymes at each step: E1 = 2; E2 = 40; E3 = 617+ E3 determines which proteins are ubiquinated.

How Are Proteins Targeted for Ubiquination? The E3 Enzyme (Ubiquitin Ligase) is the determinant.

o The N-Terminal Rule.o PEST Sequences (Pro-Glu-Ser-Thr).o Cyclin Destruction Boxes (Cell Cycle Proteins).

Deficiency of E3 Protein Juvenile (early onset) Parkinson’s is attributed to a defective E3 Gene. Proteins are not appropriately targeted for destruction and build up in the cell.

Excess of E3 Protein HPV encodes a protein that activates a specific E3 enzyme. This enzyme ubiquitinates the tumor suppressor P53 and other proteins controlling DNA repair. These proteins are prematurely destroyed resulting in less control over cell growth. This E3 activation is seen in over 90% of cervical carcinomas.

Proteasome Inhibition (2 Drugs) Velcade (Bortezomib) & Carfilzomib.

Velcade (Bortezomib) Inhibits all three protease activities in the proteasome. Used to treat multiple myeloma. Complete responses have been obtained in pts with rapidly advancing disease. Alleviates excessive proteasome-based degradation of pro-apoptotic factors in the cell.

Carfilzomib Inhibits the chymotrypsin-like activity in the proteasome. Derived from epoxomicin – a naturally occurring selective proteasome inhibitor. Used in patients with relapsed and refractory multiple myeloma. An alternative for patients who are refractory to Bortezomib.

Describe the main types of amino acid transport systems in the body and some key deficiencies.

Amino Acid Transport

Specific transporters are present on the intestinal cells to take up amino acids and the smallest peptides.

The final digestion of these peptides is accomplished by endopeptidases, dipepdidases, and aminopeptidases found on the cells in the intestine.


The concentration of free AAs in the ECF is lower than that within the cells of the body. In order to maintain this gradient, ATP is used to move AAs from the ECS into cells. There are 7 AA transport systems (2 Types): Sodium Dependent and Sodium Independent. The transporters can have overlapping specificities for AAs. The distribution of transporters among cell types differs.

Sodium Dependent AA Transport Utilize an extracellular gradient of Na to drive AA transport. Typically used for Fast Response, or AAs with high intracellular gradients.

Hartnup Disease Autosomal recessive defect. 1 in 24,000. Cause: Impaired neutral AA transport in intestine and kidney. Result: Poor AA (Tryptophan) absorption in intestine and reabsorption in the kidneys. Phenotypic Manifestation: Sunlight sensitivity, pellagra-like symptoms.

o Dermatitis, Diarrhea, and Dementia. Treatment: High-protein diet; supplementation with niacin.

Cystinuria Autosomal recessive defect. 1 in 7,000. Cause: A deficient in an AA transport system (Cys, Orn, Arg, Lys) – “COAL” Result: AAs in the urine are poorly reabsorbed. Phenotypic Manifestation: Formation of kidney stones (calculi). Treatment: Prevention of recurrent stone formation.

o Restrict methionine intake – A precursor of cysteine.o Drinking lots of water. Drugs to prevent cysteine formation.

Understand the function of aminotransferases and their diagnostic value.

In The Early Fasting State… Hepatic glycogen is used to maintain blood glucose for up to 8-12 hours. The Cori Cycle is active, pyruvate and lactate are no longer used for fatty acid synthesis.

o Instead support the formation of glucose. The Alanine Cycle is active, where C and N atoms from muscles Liver.

o In exchange the Liver sends the muscles glucose.

The Glucose-Alanine Cycle Cori Cycle permits remove of lactate from muscle so that it can be processed by other tissues. Glucose-Alanine Cycle does the same for excess nitrogen when muscles use AA as fuel source. Liver: Can use the urea cycle to dispose of excess nitrogen. Muscle: Lacks the enzymes of the urea cycle to dispose of excess nitrogen. Alanine and Glutamine transport excess nitrogen out of muscle!

In The Fasting State… No fuel is available in the gut. Glycogen is nearly depleted after 10-12 hours. The body is dependent on hepatic gluconeogenesis from Lactate (Cori), Alanine, and Glycerol. Since fats cannot supply net glucose, it is obtained from AAs (Skeletal Muscle Protein).

Response to Altered Conditions During cachexia, liver is removing AAs from plasma at an elevated rate.


This promotes muscle hydrolysis by drawing out muscle AAs. High glucagon (fasting state) increases liver AA utilization. During acidosis, liver bypasses urea cycle (to conserve bicarb).

o By sending glutamine to kidney to be acted on by glutaminase.

What do we do with the AAs we get from diet or muscle breakdown? Use them to build other proteins or in other biosynthetic reactions. Metabolize the excess to form glucose, glycogen, fatty acids, TCA intermediates…

What is the 1 st thing that needs to be done in converting AAs into C-based metabolic intermediates? The amino group must be removed!!!

The most common method = Aminotransferases or Transaminases.

The amino groups from amino acids are transferred to alpha-keto acids, creating two things. A new amino acid. A new keto acid.

Many alpha-amino groups are funneled to alpha-ketoglutarate and oxaloacetate. Forming glutamate and aspartate respectively.

Aminotransferases (Transaminases) Are generally named after the specific amino group donor since acceptor is alpha-ketoglutarate. ALANINE AMINOTRANSFERASE (ALT)

o Present in numerous tissue.o Transfers amino group of alanine to alpha-ketoglutarate.o Results in the formation of pyruvate and glutamate respectively.o During AA catabolism, ALT synthesizes glutamate – collecting nitrogen from alanine.

ASPARATE AMINOTRANSFERASE (AST)o The exception in funneling amino groups to glutamate.o Transfers amino group of glutamate to oxaloacetate.o During AA catabolism, AST synthesizes aspartate Urea Cycle

Aminotransferases contain the prosthetic group PLP derived from pyridoxine (Vitamin B6).

Diagnostic Values of Aminotransferases Presence of aminotransferase in plasma is indicative of cell disruption or lysis. They are elevated in liver disease.


ALT – Alanyl Aminotransferaseo Viral Hepatitiso Toxic Injury

More AST in liver but ALT more specific to the liver. Ratio of ALT/AST is indicative of damage.

o AST:ALT > 2 is indicative of severe hepatic necrosis or alcoholic hepatic disease.o AST:ALT < 1 is indicative of acute non-alcohol related condition (Viral Hepatitis).

Glutamate Dehydrogenase Glutamate Alpha-Ketoglutarate Oxidatively deaminates the AA Glutamate to form the keto acid Alpha-Ketoglutarate. Toxic ammonium is produced. Found in the mitochondria. Can use either NAD+ or NADP+.

Three Mechanisms for Removing the Amino Group form AAs Transamination – The most common method.

o The Amino Group of the AA is transferred to a keto acid. Usually Alpha-Ketoglutarate or Oxaloacetate.

Oxidative Deamination – The AA is oxidized and ammonia is produced.o While another compound, FMN, NAD+, etc… is reduced.

Nonoxidative Deamination – This is only for hydroxyamino acids.o Serine and Threonine.o The keto acid and ammonia are formed.

Know how nitrogen in the form of amines is buffered in the body.


The Fumarate is recycled through the TCA to generate more oxaloacetate for transamination to aspartate (or use in gluconeogenesis).

Know how nitrogen in the form of amines is buffered in the body.

Explain some potential biochemical effects of hyperammonemia.

Excessive levels of NH3 are toxic, potential mechanisms for toxicity include: Increase in pH to damaging levels. Inhibition of oxidative phosphorylation. Interference with redox balance.

Ammonia & Hyperammonemia Liver Dysfunction (Cirrhosis) can lead to elevated ammonia in the blood. When it builds up (>60 uM) it diffuses into cells and across the BBB.

Elevated NH3 (Hyperammonemia) Alpha-Ketoglutarate Glutamate Glutamine. Low Alpha-Ketoglutarate Inhibition of Citric Acid Cycle. High Glu and Glu-derived neurotransmitters. Neurologic disease, confusion, coma, death.

Primary Hyperammonemia = Caused by deficiency in the Urea Cycle.Secondary Hyperammonemia = Caused by deficiency elsewhere.Describe the process of the urea cycle and understand the biochemical bases of enzymatic deficiencies and treatments in the pathway.


The Urea Cycle Is linked with the Citric Acid Cycle, as well as gluconeogenesis. The Fumarate created in the Urea Cycle can be converted to oxaloacetate. Oxaloacetate can be used to create glucose via gluconeogenesis (or aspartate via transamination).

UCDs present in newborns who appear well for the first 24 to 48 hours after birth. The infant becomes symptomatic after feeding has started because human milk or formula has a lot of protein.

General Characteristics Hyperammonemia – Urea is the main route for removal of ammonia. Encephalopathy – Disruption of neuronal signaling / osmotic pressures. Respiratory Alkalosis – Stimulation of central respiratory drive.

UCDs Diagnosis For CPS (Carbamoyl Phosphate Synthetase) & OTC (Ornithine Transcarbamoylase) Deficiency

o High Concentration of orotic acid ↑↑↑ in OTC o Low Concentration of orotic acid ↓↓↓ in CPS.

For AS (Argininosuccinate Synthetase) and AL (Argininosuccinate Lyase) Deficiencyo AS = Citrulline 1-5 mM (Normal is 10-20 uM).o AL = High Concentration of Argininosuccinate.

UCDs Treatment Limit protein intake. Reduce bacterial producers of ammonia in the gut (Antibiotics, Acidifying Agents). Administer compounds that tie up ammonia directly.

BUPHENYL (Sodium Phenylbutyrate)


FDA-approved oral medication for the chronic adjunctive management of hyperammonemia in pts with CPS/OTC/AS deficiencies. It’s a pro-drug that’s rapidly metabolized to phenylacetate, which conjugates with glutamine, forming phenylacetylglutamine, which is excreted.

When Hyperammonemia is Present – Alpha-Ketoacids can be administered therapeutically. Replaces AA in low protein diet and lowers ammonia concentrations.

Understand the biochemical bases behind deficiencies of amino acid metabolism.

Spastic tetraplegia, seizures, psychomotor deficits, hyperactivity, growth failure. Clinical manifestations occur in first year of life: irritability, uncontrolled crying, anorexia, vomiting, and delayed development. Lab findings: Mild hyperammonemia (3-4X normal), Hyperargininemia (up to 1.5mM). Increased levels of Orn, Arg, Lys, and Cys. High levels of Arg, Orn, Asp, Thr, Gly, and Met in CSF without explanation. Mitochondrial lack of ornithine may result in buildup of CP and release into cytosol resulting in increase of pyrimidine synthesis and orotic aciduria.

Treatment: Dietary restriction of arg and other protein to decrease flux through urea cycle.


Cystinuria – Deficiency in proteins of the transport systems for cysteine and dibasic AAs in the kidney.Hartnup Disease – Impaired neutral AA transport in intestine and kidney.Phenylketonuria – Deficiency of phenylalanine hydroxylase (Hydroxylates Phenylalanine).Alkaptonuria – Deficiency of homogentisate oxidase (degrades Homogentisic acid).Maple Syrup Urine Disease – Deficiency of branched chain alpha-ketoacid enzyme complex.Albinism – Type 1 is a deficiency in Tyrosinase (Part of a pathway for melanin production).Homocystinuria – Deficiency in Cystathionine synthases (Degrades Homocysteine)

Degradation of Branched-Chain Amino Acids

These AAs are currently used to clinically aid in the recovery of burn victims.Branched Chain Amino Acids (BCAAs)


INTRODUCTION TO PROTEIN METABOLISM

Understand the importance of protein turnover for the maintenance of structure and function.

Protein Half Life (T½) Time required for 50% of the mass of that protein to be degraded and re-made. Turnover rate = Fraction of its total amount. FTR (Fractional Turnover Rate) = %/D


Oxidative Stress Theory of Aging/Disease Related to the accumulation of oxidative damage in various macromolecules (DNA, Protein). Decreased FTR of proteins occurs with age in humans.

Describe protein balance, the contributions to protein turnover and the effect of nutritional state.


Skeletal Muscle and liver account for the large majority of whole-body protein turnover (>50%)

Describe the molecular determinants of protein synthesis and breakdown and how they are influenced by nutritional stimuli.


Understand the basis for RDA values for protein intake.


AMINO ACID METABOLISM III

Learn which amino acids are essential.

Amino Acids that humans can’t synthesize are known as essential AAs. Cysteine and Tyrosine are “conditionally essential” Cysteine is derived from Serine and requires sulfur derived from the EAA Methionine. Tyrosine is derived from the EAA Phenylalanine via hydroxylation.

PVT TIM HALL Phenylalanine, Valine, Threonine. Tryptophan, Isoleucine, Methionine. Histidine, Arginine, Leucine Lysine.


ARGININE Is essential in growing animals that can’t obtain sufficient Ornithine in the Urea Cycle. Along with Arginine, Cysteine, Tyrosine, Histidine, and Taurine are Semi EAAs in kids.

TAURINE: Is involved in the formation of bite salts. It is not technically an Amino Acid.

What makes an essential AA essential? Higher energy requirement for the synthesis of EAAs. Multiple step synthesis. Different enzymes for each step. Lots and lots of machinery and energy needed.

o Notable Exception: Proline – 39 ATP needed.

Know the synthetic origins of some of the nonessential amino acids.

Understand the role that sulfur-containing amino acids and the methyl cycle play in metabolism.

Proline and Arginine are derived from Glutamate.

Serine / Glycine are obtained from Glucose or Glycerol.

Conditionally Essential

Sulfur atom of Cysteine comes from EAA Methionine with the C-skeleton coming from Serine.

Tyrosine is obtained by the hydroxylation of EAA phenylalanine.


Sulfur Amino Acids (Cys, Met, Hcy) Cysteine is a NEAA whose availability is dependent upon Methionine intake. Human methionine and cysteine requirements are poorly defined. Elevated blood Homocysteine levels correlate with cardiovascular disease risk.

Methionine and Cysteine Objectives The methionine/activated methyl cycle. The cofactors involved (B6, B9, & B12). How cysteine is derived from the methionine cycle.

S-Adenosylmethionine

Metabolism of Propionyl-CoA Unlike Acetyl-CoA, Propionyl-CoA can be a substrate for gluconeogenesis.

These reactions constitute the activated methyl cycle, where methyl groups enter the cycle when homocysteine is converted into methionine, which is adenylated to create high-energy SAM molecules. The high-energy methyl groups can be donated to a variety of acceptors, creating S-adenosylhomocysteine, which can be hydrolyzed to regenerate homocysteine for another round of the cycle.


Problems with the biotin or B12 dependent enzyme lead to:o Metabolic Acidosis.o Mental Deficits.

Tetrahydrofolate Tetrahydrofolate is a carrier of 1C units used in a variety of synthetic/degradative reactions. The molecule is formed from a substituted pteridine moiety, p-aminobenzoate, and a chain of one

or more glutamate residues. While mammals can synthesize the pteridine ring, they cannot conjugate it to the other two units and therefore must obtain it from their diets or microorganisms in their intestinal tracts.

The precursor molecule, folic acid or folate, is vitamin B9.

Homocysteine Degradation IS Cysteine Synthesis Via Transsulfuration 1st Step – Condensation with Serine.


o To form Cystathionine.o By Cystathionine Synthases.

2nd Step – Split Cystathionine.o To form Cysteine, alpha-ketobutyrate and NH3.o Cysteine gets the Serine C.o By Cystathionase.

No Vitamin B6 No PLP No Cysteine ↑↑↑ Homocysteine.

Know the synthetic origins of some of the specialized metabolites derived from amino acids.


Specialized Products Derived From AAs AAs are precursors for numerous nitrogen-containing compounds:

o Thyroxineo Phospholipidso Coenzymeso Hormoneso Porphyrinso Neurotransmitterso Purineso Pyrimidines

Porphyrins All the C & N come from:

o Glycine and Succinyl CoA. Bind Ferrous and Ferric Iron.


REGULATION OF BODY PROTEIN STORES: ROLE OF PHYSICAL EXERCISE


Describe muscle protein balance, its key nutritional and hormonal regulators and the cellular/molecular mechanisms underlying their effects.

Describe the effects of non-nutritional, hormonal factors on muscle protein balance.


Describe the effect of physical activity on muscle fiber size, the hormonal factors that regulate muscle hypertrophy and the cellular/mechanisms underlying these effects.


Nutritional Significance Muscle protein stores serve as a reservoir during times of stress and trauma. Depletion of this

substrate store can negatively impact the metabolic response to injury/infection and can lead to increased morbidity/mortality.


SEPSIS LECTURE

SIRS: Is a clinical syndrome that is a form of unregulated inflammation. The term SIRS has routinely been associated with both infectious processes (sepsis) and

noninfectious insults, such as an autoimmune disorder, pancreatitis, vasculitis, thromboembolism, burns, or surgery.

SIRS was previously defined as two or more abnormalities in temperature, heart rate, respiration, or white blood cell count. However, in practice, its clinical definition and pathophysiology are non-equivocal such that SIRS and early sepsis cannot be readily distinguished.

Thus, when SIRS is suspected it should prompt an evaluation for a septic focus.

SIRS CRITERIA An individual is in SIRS when 2 or more of the following criteria are met:

o Body Temperature: < 36C or > 38C. HR > 90.o Tachypnea: RR > 20 breaths/min or and arterial partial pressure of CO2 < 32 mmHg.o Leukocytes <4000 cells/L of >12000 cells/L. (Or >10% bands).

SEPSIS A clinical syndrome as a result of the loss of regulation of an inflammatory response in the

setting of an infection. Diagnostic Criteria for Sepsis requires a documented or suspected site of infection as well as one of the following:

SEVERE SEPSIS Severe Sepsis refers to sepsis-induced tissue hypoperfusion or organ dysfunction with any of

the following thought to be due to the infection:o Lactate above upper limits of laboratory normal.o Urine Output < 0.5 mL/kg/hr for > 2 hours despite adequate fluid resuscitation.o Acute lung injury with PaO2/FIO2 <250 in the absence of pneumonia as infection source.o Acute lung injury with PaO2/FIO2 <200 in the presence of pneumonia as infection

source.o Creatinine > 2 mg/dL.o Bilirubin > 2 mg/dL.o Platelet Count < 100,000.o Coagulopathy (INR > 1.5).o Sepsis-Induced Hypotension is defined as a systolic blood pressure (SBP) <90 mmHg

or mean arterial pressure (MAP) <70 mmHg or a SBP decrease >40 mmHg or less than two standard deviations below normal for age in the absence of other causes of hypotension.

SEPTIC SHOCK All of the above. Blood Pressure is non-responsive to adequate fluid hydration. Patients often require vasopressors to maintain blood pressure.


LACTATE Rather than thinking of lactate solely as a byproduct of inadequate blood perfusion, it may be

useful to consider lactate as a marker of strained cellular metabolism. For the purposes of the ED patients with sepsis or trauma, volume depletion, blood loss, septic

shock, and systemic inflammatory syndrome can alter lactate levels.

When the body experiences inadequate tissue perfusion, it undergoes anaerobic metabolism to create some energy, even in a small amount. In this case, pyruvate metabolizes to lactate.

Produces 2 APT instead of 36 produced in the Glycolytic pathway.

It also appears that lactate screening may prove beneficial even in normotensive, hemodynamically stable patients. Shapiro et al. in a study with 1,278 patients with infection, demonstrated that increasing lactate levels were associated with increased mortality.

Lactate levels less than 2.5 mmol/L were associated with a 4.9% mortality rate Lactate levels ≥ 4 mmol/L who had an in-hospital mortality of 28.4%.

A lactate concentration ≥ 4 mmol/L was 36% (95% CI 27-45%) sensitive and 92% (95% CI 90-93%) specific for any death.

Nutritional Requirements in Critically Ill Patients


GOALS: The primary goal of nutrition support therapy is to supply the substrate necessary to meet the metabolic needs of patients in whom adequate nourishment cannot be provided by mouth. These needs vary with the phase of critical illness:

Acute critical illness is characterized by catabolism exceeding anabolism. Carbohydrates are the preferred energy source during this period because fat mobilization is impaired. Nutrition support supplies the nutrients necessary to meet the demands of the catabolic state. The hope is that this will mitigate the breakdown of muscle proteins into amino acids that serve as the substrate for gluconeogenesis.

Recovery from critical illness is characterized by anabolism exceeding catabolism. Nutrition support provides substrate for the anabolic state, during which the body corrects hypoproteinemia, repairs muscle loss, and replenishes other nutritional stores.

REFEEDING SYNDROME

Refeeding Syndrome: Potentially fatal shifts in fluids and electrolytes that may occur in malnourished patients receiving artificial refeeding.

The hallmark biochemical feature of refeeding syndrome is hypophosphatemia.

The Process of Refeeding During refeeding, glycemia leads to increased insulin and decreased secretion of glucagon. Insulin stimulates glycogen, fat, and protein synthesis. This process requires phosphate and magnesium and cofactors such as thiamine. Insulin stimulates the absorption of K into the cells though the Na-K ATPase symporter.

o Which also transports glucose into the cells.o Magnesium and phosphate are also taken up into the cells.o Water follows by osmosis.

All of these processes result in a decreased in the serum levels of:o Phosphate.o Potassium.o Magnesium.

The clinical features of the refeeding syndrome occur as a result of the functional deficits of these electrolytes and the rapid change in basal metabolic rate.

PROTEIN ENERGY MALNUTRITION (PEM)

All of which were already depleted…


ADAPTATION TO FAST


INSULIN IS NUMBER ONE!!!!!!INSULIN IS NUMBER ONE!!!!!!INSULIN IS NUMBER ONE!!!!!!


REGULATION OF BODY PROTEIN REVIEW


Nutritional Significance Muscle protein stores serve as a reservoir during times of stress and trauma. Depletion of

thise substrate store can negatively impact the metabolic response to injury/infection and can lead to increased morbidity and mortaility.

PROTEIN BALANCE REVIEW SLIDES


AMINO ACID REVIEW SLIDES


TA SEPSIS REVIEW SLIDES


CHOLESTEROL METABOLISM I

Bile Acids & Salts are derived from Cholesterol and synthesized in the Liver. The majority of bile acids & salts are reabsorbed & returned to the liver, enterohepatic

circulation.


We reabsorbed about 95% of our bile (we secrete about 20 grams a day).

Bile Salt Mixed Micelle Allows hydrolysis of triglycerols to form FFAs. Also important to get cholesterol into the enterocyte.

Bile Salts Facilitate Fat Digestion & Cholesterol Absorption

Chylomicrons

Lumen of SmallIntestineAbsorptive

Epithelial Cell

LipidDigestionProducts

Resynthesis

Micelle

Lipid Digestion Products are Re-Esterified in the SER and Packaged Into Chylomicrons by the RER


Chylomicrons, synthesized by the enterocyte, transport dietary fat to extra-hepatic tissues and bypass the liver; cholesterol is ultimately delivered to the liver.

Porta

lBlood

La c te a l

Sm o o thM usc le

C hylo m ic ro ns

Lume

n of Sm

all

Intestine

Ep ithe lia l C e ll

Extra c e llula rSp a c e

Lym p ha ticVa lve

Exo c yto sis

Lipid Intravascular Transport: Lipoproteins

Chylomicron is what delivers cholesterol to the liver.


Lipoproteins vary in diameter from 5-1000 nm. Each type contains a neutral lipid core surrounded by a layer of charged and polar residues on its surface that enables it to be transported in blood.

Intravascular Transport of Digested and Absorbed Fat (and Cholesterol) Chylomicrons:

o Synthesized in the intestine.o Contain Apolipoprotein B48 (structure protein of all chylomicrons).o Contain Apolipoprotein CII (activates extrahepatic lipoprotein lipase).o Approximaetly 100-1000 nm in diameter.o 86% Triglycerides, 3% Cholesterol Esters.

Liver Does Not Contain Lipoprotein Lipase.

How the liver regulates and maintains homeostatic control of cholesterol use and distribution:


1. The metabolic routes of dietary cholesterol, i.e. its packaging into chylomicrons, transport to liver and its use in liver metabolism:

Five Main Lipoprotein Classes HDL Detoxify Cholesterol by turning it

into a cholesterol ester – All Cells Will Contain ACAT!


LDL IDL VLDL Chylomicron

Chylomicron Retention Disease: Deficiency/defect in Apo-B48 Failure to incorporate apo-B48 into chylomicrons – prevents exocytosis into lymph; Malabsorption of dietary fats, cholesterol and fat-soluble vitamins; Signs/symptoms appear in first few months after birth; failure to thrive,

o Diarrhea; and steatorrhea; ultimate impaired function of the nervous system.

Detoxify Cholesterol by turning it into a cholesterol ester – All Cells Will Contain ACAT!

How the liver regulates and maintains homeostatic control of cholesterol use and distribution:


2. The regulation of bile salt synthesis:

Cytochrom P450 Electron Transport Systems

Enterohepatic Circulation of Bile Salts: An Extremely Efficienct Process

How the liver regulates and maintains homeostatic control of cholesterol use and distribution:3. The major pathways responsible for phospholipid biosynthesis:


Major Phospholipids


GALLSTONES

Risk Factors For Gallstones Age, Female, Pregnancy Estrogen Therapy, Obesity Hypertriglyceridemia, Genetics Drugs, Diabetes, Cirrhosis Crohn’s Disease, Parasites

BILE FACTS Bile Salts. Phospholipids – 95% Lecithin. Cholesterol – From liver, little from diet. Bilirubin.

BILE FACTS CONTINUED 85% Water. 500-1000 ml per day. Vagal stimulation increases flow. Splanchnic vasoconstriction decreases hepatic blood flow and bile secretion. Secretin, CCK, gastrin, and Glucagon ↑↑↑ flow by ↑↑↑ water and electrolytes.

Gallbladder Function Store and concentrate bile during fasting. Allow for its coordinated release in response to a meal. Absorption. Secretion. Motor function.

GB Function – Absorption Greatest absorptive capacity of any organe. Bile concentrated 5-fold. Active Na-Cl transport. Passive water absorption by osmosis. Concentration of bile affects Ca and Cholesterol solubilities.

GB Function – Secretion Glycoproteins from the glands of the gallbladder neck and cystic duct. Mucin gel protects mucosa. Prostaglandins stimulate mucus production. Mucin glycoproteins – pronucleating agents for cholesterol gallstones.

GB Function – Motor Function Filling facilitated by tonic contraction of the Sphincter of Oddi. Partial emptying and filling. Coordinated emptying – CCK, and other hormones and neural influences. Vagal = Stimulatory / Splanchnic = Inhibitory.

BILE DUCTS Bile modified by the absorption and secretion of water and electrolytes.

Protective Factors Vitamin C Caffeinated Coffee Vegetable Protein Poly and Monounsaturated Fats


Secretin – Active secretion of Chloride rich fluid. CCK and Gastrin also stimulate secretion. Epithelium capable of absorbing water and electrolytes.

Sphincter of Oddi Function High pressure zone between BD and Duodenum. Prevents regurgitation of duodenal contents. Relaxed by Meal – CCK. Relaxation coordinated with Phase III MMC.

GALLSTONES Cholesterol. Black Pigment. Brown Pigment.

Cholesteral Gallstones Cholesterol saturation. Nucleation. Stone growth.

Cholesterol Solubility in Bile Affected by bile concentration. Micellar fraction increased – But stabolity of cholesterol vesicles decreased. Net effect is nucleate cholesterol.

Pigment Gallstones Black Pigment Stones

o Hemolysis or cirrhosis. GB stones. Insoluble conjugated bilirubin binds with Calcium.


Brown Pigment Stoneso GP or ducts. Bacterial glucuronidase hydrolyses conjugated bilirubin to insoluble

bilirubin which binds the Calcium.

Biliary Colic (Sudden Obstruction) T5-9 Distribution. RUQ, midepigastric, circumferential. Radiate to lower tip of Right scapula. Not relieved by antacids. 30 minutes to 8 hours. Acute increase tension in GB muscle.

Cholecystectomy 1,000,000 a year. Observe asymptomatic patients. Risk for symptoms – 1-2%/year. Serious complications rarely occur without symptoms.

Acute Cholecystitis 10-20% of symptomatic patients. Saturated bile activates inflammatory mediators – Prostraglandins, Lysolecithin. Prostaglandins stimulate secretion of water and mucin leading to increased luminal pressure. Edematous GB wall from venous and lymphatic obstruction leads to ischemia.

Risk Factors for Bacterio in Bile Age 55-65 years. Immuno-compromised (HIV, Steroids, Diabetes, Transplants).

Complications of Cholecystitis Emphysematous cholecystitis. Empyema. Perforation. Hydrops.

Non-Surgical Therapy Oral Dissolution – Ursodeoxycholic Acid Chemical Dissolution Therapy

o MTBE (No longer done) Shock wave lithotripsy.

o Not as effective as surgical therapy. High recurrence rates.

Porcelain Gallbladder Calcified GB Wall. Higher Risk of Cancer.


Cholangitis Treatment IV Fluids and antibiotics. Emergency biliary decompression in patients with septic shock. ERCP draining preferred as initial step if possible.

o Endoscopic Retrograde Cholangiopancreatography.

Liver Flukes Asia (Thailand) Humans infected by consuming undercooked fish. Adult worms inhabit the bile ducts where they lay eggs. Induce a chronic inflammatory state. Leads to malignant transformation bile duct epithelium. Associated with brown pigment stones.

Flipping The Classroom

Cholangitis Charcot’s Triad

o Fever +o Jaundice +o RUQ PAIN

Reynold’s Pentado Charcot’s +o Shock +o Delirium

Bacterial contamination plus increased biliary pressure!

Study Guide Block Nutrition

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