Colloquim 2 Flashcards
The digestion of dietary lipids begins in the stomach and continues in the small intestine.
The hydrophobic nature of lipids requires that the dietary lipids, particularly those that contain long-chain length fatty acids (LCFAs), be emulsified for efficient degradation.
Triacylglycerols (TAG) obtained from milk contain short- to medium-chain length fatty acids that can be degraded in the stomach by the acid lipases (lingual lipase and gastric lipase).
Cholesteryl esters (CEs), phospholipids (PLs), and TAG containing LCFAs are degraded in the small intestine by enzymes secreted by the pancreas.
The most important of these enzymes are pancreatic lipase, phospholipase A2, and cholesterol esterase.
The dietary lipids are emulsified in the small intestine using peristaltic action and bile salts, which serve as detergents.
The primary products resulting from enzymatic degradation of dietary lipid are 2-monoacylglycerol, unesterified cholesterol, and free fatty acids. These compounds, plus the fat-soluble vitamins, form mixed micelles that facilitate the absorption of dietary lipids by intestinal mucosal cells (enterocytes).
These enterocyte cells resynthesize TAG, CE, and PL using LCFAs and also synthesize protein (apolipoprotein B-48), all of which are then assembled with the fat-soluble vitamins into lipoprotein particles called chylomicrons. Short- and medium-chain fatty acids enter blood directly.
Chylomicrons are released into the lymph, which carries them to the blood, where their lipid core is degraded by lipoprotein lipase (with apolipoprotein C-II as the coenzyme) in muscle and adipose tissues. Thus, dietary lipids are made available to the peripheral tissues.
Problems with fat absorption cause steatorrhea. A deficiency in the ability to degrade chylomicron components, or remove their remnants after TAG has been removed, results in accumulation of these particles in blood.
Which one of the following statements about the digestion of lipids is correct?
D. Patients with cystic fibrosis have difficulties with digestion because their thickened pancreatic secretions are less able to reach the small intestine, the primary site of lipid digestion.
D. Patients with cystic fibrosis, a genetic disease due to a deficiency of a functional chloride transporter, have thickened secretions that impede the flow of pancreatic enzymes into the duodenum.
Emulsification occurs through peristalsis, which provides mechanical mixing, and bile salts that function as detergents.
Colipase restores activity to pancreatic lipase in the presence of inhibitory bile salts that bind the micelles.
Cholecystokinin is the hormone that causes contraction of the gallbladder and release of stored bile, and secretin causes release of bicarbonate.
Chylomicron formation requires synthesis of apolipoprotein B-48.
Which one of the following statements about the absorption of lipids from the intestine is correct?
B. The triacylglycerol carried by chylomicrons is degraded by lipoprotein lipase to fatty acids that are taken up by muscle and adipose tissues and glycerol that is taken up by the liver.
B. The triacylglycerols (TAGs) in chylomicrons are degraded to fatty acids and glycerol by lipoprotein lipase on the endothelial surface of capillaries in muscle and adipose, thus providing a source of fatty acids to these tissues for degradation or storage and providing glycerol for hepatic metabolism.
In the duodenum, TAG are degraded to one 2-monoacyl-glycerol + two free fatty acids that get absorbed.
Medium- and short-chain fatty acids enter directly into blood (not lymph), and they neither require micelles nor get packaged into chylomicrons.
Because chylomicrons contain dietary lipids that were digested and absorbed, a defect in fat absorption would result in decreased production of chylomicrons.
Generally a linear hydrocarbon chain with a terminal carboxyl group, a fatty acid can be saturated or unsaturated.
Two fatty acids are dietary essentials: linoleic and α-linolenic acids.
Fatty acids are synthesized in the cytosol of liver following a meal containing excess carbohydrate and protein. Carbons used to synthesize fatty acids are provided by acetyl coenzyme A (CoA), energy by ATP, and reducing equivalents by nicotinamide adenine dinucleotide phosphate ([NADPH] provided by the pentose phosphate pathway and malic enzyme.
Citrate carries two-carbon acetyl units from the mitochondrial matrix to the cytosol. The regulated step in fatty acid synthesis is catalyzed by biotin-requiring acetyl CoA carboxylase (ACC). Citrate allosterically activates ACC and long-chain fatty acyl CoAs inhibit it.
ACC can also be activated by insulin and inactivated by adenosine monophosphate–activated protein kinase (AMPK) in response to epinephrine, glucagon, or a rise in AMP.
The remaining steps in fatty acid synthesis are catalyzed by the multifunctional enzyme, fatty acid synthase, which produces palmitoyl CoA by adding two-carbon units from malonyl CoA to a series of acyl acceptors.
Fatty acids can be elongated and desaturated in the endoplasmic reticulum (ER).
When fatty acids are required for energy, adipocyte hormonesensitive lipase (activated by epinephrine, and inhibited by insulin), along with other lipases, degrades stored triacylglycerol (TAG).
The fatty acid products are carried by serum albumin to the liver and peripheral tissues, where oxidation of the fatty acids provides energy.
The glycerol backbone of the degraded TAG is carried by the blood to the liver, where it serves as an important gluconeogenic precursor.
Fatty acid degradation (β-oxidation) occurs in mitochondria. The carnitine shuttle is required to transport long-chain fatty acids from the cytosol to the mitochondrial matrix. A translocase and the enzymes carnitine palmitoyltransferases (CPT) I and II are required.
CPT-I is inhibited by malonyl CoA, thereby preventing simultaneous synthesis and degradation of fatty acids.
In the mitochondria, fatty acids are oxidized, producing acetyl CoA, nicotinamide adenine dinucleotide (NADH), and flavin adenine dinucleotide (FADH2).
The first step in the β-oxidation pathway is catalyzed by one of four acyl CoA dehydrogenases, each with chain-length specificity.
Medium-chain fatty acyl CoA dehydrogenase (MCAD) deficiency causes a decrease in fatty acid oxidation (process stops once a medium chain fatty acid is produced), resulting in hypoketonemia and severe hypoglycemia.
Oxidation of fatty acids with an odd number of carbons proceeds two carbons at a time (producing acetyl CoA) until three-carbon propionyl CoA remains. This compound is carboxylated to methylmalonyl CoA (by biotin-requiring propionyl CoA carboxylase), which is then converted to succinyl CoA (a gluconeogenic precursor) by vitamin B2requiring methylmalonyl CoA mutase.
A genetic error in the mutase or vitamin B12 deficiency causes methylmalonic acidemia and aciduria.
β-Oxidation of very-long-chain fatty acids and α-oxidation of branched-chain fatty acids occur inthe peroxisome.
ω-Oxidation, a minor pathway, occurs in the ER.
Liver mitochondria can convert acetyl CoA derived from fatty acid oxidation into the ketone bodies acetoacetate and 3-hydroxybutyrate. Peripheral tissues possessing mitochondria can oxidize 3-hydroxybutyrate to acetoacetate, which can be reconverted to acetyl CoA, thereby producing energy for the cell.
Unlike fatty acids, ketone bodies are utilized by the brain and, therefore, are important fuels during a fast. Because the liver lacks the ability to degrade ketone bodies, it synthesizes them specifically for the peripheral tissues.
Ketoacidosis occurs when the rate of ketone body formation is greater than the rate of use, as is seen in cases of uncontrolled type 1 diabetes mellitus.
When oleic acid, 18:1(9), is desaturated at carbon 6 and then elongated, what is the product?
D. 20:2(8,11)
D. Fatty acids are elongated in the endoplasmic reticulum by adding two carbons at a time to the carboxylate end (carbon 1) of the molecule. This pushes the double bonds at carbon 6 and carbon 9 further away from carbon 1. 20:2(8,11) is an n-9 (ω-9) fatty acid.
A 4-month-old child is being evaluated for fasting hypoglycemia. Laboratory tests at admission reveal low levels of ketone bodies, free carnitine, and acylcarnitines in the blood. Free fatty acid levels in the blood were elevated. Deficiency of which of the following would best explain these findings?
B. Carnitine transporter
B. A defect in the carnitine transporter (primary carnitine deficiency) would result in low levels of carnitine in the blood (as a result of increased urinary loss) and low levels in the tissues.
In the liver , this decreases fatty acid oxidation and ketogenesis. Consequently, blood levels of free fatty acids rise.
Deficiencies of adipose triglyceride lipase would decrease fatty acid availability.
Deficiency of carnitine palmitoyltransferase I would result in elevated blood carnitine.
Defects in any of the enzymes of β-oxidation would result in secondary carnitine deficiency, with a rise in acylcarnitines
A teenager , concerned about his weight, attempts to maintain a fat-free diet for a period of several weeks. If his ability to synthesize various lipids were examined, he would be found to be most deficient in his ability to synthesize:
D. prostaglandins
D. Prostaglandins are synthesized from arachidonic acid. Arachidonic acid is synthesized from linoleic acid, an essential fatty acid obtained by humans from dietary lipids. The teenager would be able to synthesize all other compounds(Cholesterol, glycolipids, phospholipids and tricylglycerol) but, presumably, in somewhat decreased amounts
A 6-month-old boy was hospitalized following a seizure. History revealed that for several days prior , his appetite was decreased due to a “stomach virus.” At admission, his blood glucose was 24 mg/dl (age-referenced normal is 60–100). His urine was negative for ketone bodies and positive for a variety of dicarboxylic acids. Blood carnitine levels were normal. A tentative diagnosis of medium-chain fatty acyl coenzyme A dehydrogenase (MCAD) deficiency is made. In patients with MCAD deficiency, the fasting hypoglycemia is a consequence of:
A. decreased acetyl coenzyme A production
A. Impaired oxidation of fatty acids less than 12 carbons in length results in decreased production of acetyl coenzyme (CoA), the allosteric activator of pyruvate carboxylase, a gluconeogenic enzyme, and, thus, glucose levels fall.
Acetyl CoA can never be used for the net synthesis of glucose.
Acetoacetate is a ketone body, and with medium-chain fatty acyl CoA dehydrogenase deficiency(MCAD), ketogenesis is decreased as a result of decreased production of the substrate, acetyl
CoA.
Impaired fatty acid oxidation means that less ATP and nicotinamide adenine dinucleotide are made, and both are needed for gluconeogenesis
Explain why with Zellweger syndrome both very-long-chain fatty acids (VLCFAs) and phytanic acid accumulate, whereas with X-linked adrenoleukodystrophy, only VLCFAs accumulate.
Zellweger syndrome is caused by an inability to target matrix proteins to the peroxisome. Therefore, all peroxisomal activities are affected because functional peroxisomes are not able to be formed.
In X-linked adrenoleukodystrophy, the defect is an inability to transport very-longchain fatty acids into the peroxisome, but other peroxisomal functions, such as α-oxidation, are normal.
Phospholipids are polar, ionic compounds composed of an alcohol (for example, choline or ethanolamine) attached by a phosphodiester bond to either diacylglycerol (DAG), producing phosphatidylcholine or phosphatidylethanolamine, or to the amino alcohol sphingosine.
Addition of a long-chain fatty acid to sphingosine produces a ceramide. Addition of a phosphorylcholine produces the phospholipid sphingomyelin.
Phospholipids are the predominant lipids of cell membranes. Nonmembrane phospholipids serve as components of lung surfactant and bile.
Dipalmitoylphosphatidylcholine, also called dipalmitoyl lecithin, is the major lipid component of lung surfactant.
Insufficient surfactant production causes respiratory distress syndrome.
Phosphatidylinositol (PI) serves as a reservoir for arachidonic acid in membranes. The phosphorylation of membrane-bound PI produces phosphatidylinositol 4,5-bisphosphate (PIP2). This compound is degraded by phospholipase C in response to the binding of a variety of neurotransmitters, hormones, and growth factors to membrane G protein–coupled receptors. The products of this degradation, inositol 1,4,5-trisphosphate (IP3) and DAG mediate the mobilization of intracellular calcium and the activation of protein kinase C, which act synergistically to evoke cellular responses.
Specific proteins can be covalently attached via a carbohydrate bridge to membrane-bound phosphatidylinositol (glycosyl phosphatidylinositol, or GPI), forming a GPI anchor .
A deficiency in the synthesis of GPI in hematopoietic cells results in a hemolytic disease, paroxysmal nocturnal hemoglobinuria.
The degradation of phosphoglycerides is performed by phospholipases found in all tissues and pancreatic juice.
Sphingomyelin is degraded to aceramide plus phosphorylcholine by the lysosomal enzyme sphingomyelinase, a deficiency of which causes Niemann-Pick (A + B) disease.
Glycosphingolipids are derivatives of ceramides to which carbohydrates have been attached. When one sugar molecule is added to the ceramide, a cerebroside is produced. If an oligosaccharide is added, a globoside is produced. If an acidic N-acetylneuraminic acid molecule is added, a ganglioside is produced.
Glycosphingolipids are found predominantly in cell membranes of the brain and peripheral nervous tissue, with high concentrations in the myelin sheath. They are antigenic. Glycolipids are degraded in the lysosomes by acid hydrolases. A deficiency of any one of these enzymes produces a sphingolipidosis, in which a characteristic sphingolipid accumulates.
Prostaglandins (PGs) , thromboxanes (TXs), and leukotrienes (LTs) are produced in very small amounts in almost all tissues, act locally, and have an extremely short half-life. They serve as mediators of the inflammatory response.
Arachidonic acid is the immediate precursor of the predominant class of PGs in humans (those with two double bonds). It is derived by the elongation and desaturation of the essential fatty acid linoleic acid and is stored in the membrane as a component of a phospholipid, generally PI.
Arachidonic acid is released from the phospholipid by phospholipase A2 (inhibited by cortisol).
Synthesis of the PGs and TXs begins with the oxidative cyclization of free arachidonic acid to yield PGH2 by prostaglandin endoperoxide synthase (PGH synthase), an endoplasmic reticulum membrane protein that has two catalytic activities: fatty acid cyclooxygenase (COX) and peroxidase.
There are two isozymes of PGH synthase: COX-1 (constitutive) and COX-2 (nonconstitutive). Aspirin irreversibly inhibits both.
Opposing effects of PGI2 and TXA2 limit clot formation.
LTs are linear molecules produced from arachidonic acid by the 5-lipoxygenase pathway. They mediate allergic response and are not inhibited by aspirin or other NSAIDs
Aspirin-induced asthma (AIA) is a severe reaction to nonsteroidal anti-inflammatory drugs (NSAIDs) characterized by bronchoconstriction 30 minutes to several hours after ingestion. Which of the following statements best explains the symptoms seen in patients with AIA? NSAIDs:
B. inhibit cyclooxygenase but not lipoxygenase, resulting in the flow of arachidonic acid to leukotriene synthesis.
B. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase but not lipoxygenase, so any arachidonic acid available is used for the synthesis of bronchoconstricting leukotrienes.
NSAIDs have no effect on the cystic fibrosis transmembrane conductance regulator protein protein, defects in which are the cause of cystic fibrosis.
Steroids, not NSAIDs, inhibit phospholipase A2.
Cyclooxygenase is inhibited by NSAIDs, not activated. NSAIDs have no effect on phospholipases.
Complete the table below for an individual with classic 21-α-hydroxylase deficiency relative to a normal individual
How might the results be changed if this individual were deficient in 17-αhydroxylase, rather than 21-α-hydroxylase?
21-α-Hydroxylase deficiency causes mineralocorticoids (aldosterone) and glucocorticoids (cortisol) to be virtually absent. Because aldosterone increases blood pressure, and cortisol increases blood glucose, their deficiencies result in a decrease in blood pressure and blood glucose, respectively. Cortisol normally feeds back to inhibit adrenocorticotropic hormone (ACTH) release by the pituitary, and, so, its absence results in an elevation in ACTH. The loss of 21-αhydroxylase pushes progesterone and pregnenolone to androgen synthesis, therefore, causes androstenedione levels to rise. With 17-α-hydroxylase deficiency, sex hormone synthesis would be inhibited. Mineralocorticoid production would be increased, leading to hypertension.
