Week 8 Lecture 13 PDF

Week 8 Lecture 13 Peroxisomes contain a variety of enzymes, which primarily function together to rid the cell of toxic substances, and in particular, hydrogen peroxide (a common byproduct of cellular metabolism). These organelles contain enzymes that convert the hydrogen peroxide to water, renderin...

Week 8 Lecture 13 Peroxisomes contain a variety of enzymes, which primarily function together to rid the cell of toxic substances, and in particular, hydrogen peroxide (a common byproduct of cellular metabolism). These organelles contain enzymes that convert the hydrogen peroxide to water, rendering the potentially toxic substance safe for release back into the cell. Some types of peroxisomes, such as those in liver cells, detoxify alcohol and other harmful compounds by transferring hydrogen from the poisons to molecules of oxygen (a process termed oxidation). Others are more important for their ability to initiate the production of phospholipids, which are typically used in the formation of membranes.  Peroxisomes are similar in appearance to lysosomes, another type of microbody, but the two have very different origins. Lysosomes are generally formed in the Golgi complex, whereas peroxisomes self-replicate. Unlike self-replicating mitochondria, however, peroxisomes do not have their own internal DNA molecules. Consequently, the organelles must import the proteins they need to make copies of themselves from the surrounding cytosol. The importation process of peroxisomes is not yet well understood, but it appears to be heavily dependent upon peroxisomal targeting signals composed of specific amino acid sequences. These signals are thought to interact with receptor proteins present in the cytosol and docking proteins present in the peroxisomal membrane. As more and more proteins are imported into lumen of a Illustrated in this Figure is a fluorescence digital image peroxisome or are inserted into its membrane, the of an African water mongoose skin fibroblast cell organelle gets larger and eventually reaches a stained with fluorescent probes targeting the nucleus point where fission takes place, resulting in two (red), actin cytoskeletal network (blue), and daughter peroxisomes. peroxisomes (green).  Zellweger syndrome is an autosomal recessive disorder caused by mutations in genes that encode peroxins, proteins required for the normal assembly of peroxisomes. Most commonly, patients have mutations in the PEX1, PEX2, PEX3, PEX5, PEX6, PEX10, PEX12, PEX 13, PEX14, PEX16, PEX19, or PEX26 genes. In almost all cases, patients have mutations that inactivate or greatly reduce the activity of both the maternal and paternal copies of one these aforementioned PEX genes. As a result of impaired peroxisome function, an individual's tissues and cells can accumulate very long chain fatty acids (VLCFA) and branched chain fatty acids (BCFA) that are normally degraded in peroxisomes. The accumulation of these lipids can impair the normal function of multiple organ systems, as discussed above. In addition, these individuals can show deficient levels of plasmalogens, ether-phospholipids that are especially important for brain and lung function. Characteristic facial abnormalities in a neonatal affected by peroxisomal disorders. Peroxisomal disorders are associated with characteristic facial abnormalities (high forehead, frontal A defect of functional peroxisomes results in several bossing, small face, low set ears, slanted eyes, etc.). Patients metabolic abnormalities, which in most cases can be present as floppy children, due to their decreased muscle tone detected in blood and urine. There is currently no curative (hypotonia). Developmental delay and mental retardation is common to all patients, and vision and hearing are affected therapy, but supportive care is available. very soon. In general, these children are difficult to feed. Zellweger syndrome is associated with impaired neuronal migration, neuronal positioning, and brain development. In addition, individuals with Zellweger syndrome can show a reduction in central nervous system (CNS) myelin (particularly cerebral), which is referred to as hypomyelination. Myelin is critical for normal CNS functions, and in this regard, serves to insulate nerve fibers in the brain. Patients can also show postdevelopmental sensorineuronal degeneration that leads to a progressive loss of hearing and vision. Oral Glucose Tolerance Test Elena Breda et al. Diabetes 2001;50:150-158 Design an experiment to test they hypothesis that direct insulin signaling in the liver regulates glucose production.  (a) Fed blood glucose and serum insulin concentrations were determined from 2-month- old male WT, IR(lox/lox), alb-Cre, and LIRKO mice at 2200–2300 hr (light cycle: 0700 on– 1900 off). Each bar represents the mean ± SEM of at least 12 animals of each genotype. (b) Glucose tolerance tests were performed on 2-month-old male WT, IR(lox/lox), alb-Cre, and LIRKO mice that had been fasted for 16 hr. Animals were injected intraperitoneally with 2 g/kg body weight of glucose. Blood glucose was measured immediately before injection and 15, 30, 60, and 120 min after the injection. Results are expressed as mean blood glucose concentration ± SEM from at least eight animals per genotype. (c) Insulin tolerance tests were performed on random-fed, 2-month-old male WT, IR(lox/lox), alb-Cre, and LIRKO mice (performed at 1400 hr). Animals were injected intraperitoneally with 1 U/kg body weight of human regular insulin. Blood glucose was measured immediately before injection and 15, 30, and 60 min after the injection. LIRKO: Liver Insulin Receptor knockout Results are expressed as mean percent of basal blood glucose concentration ± SEM from at least eight animals per genotype.  LIRKO: Liver Insulin Receptor knockout (a) Two-month-old male control (WT, IR(lox/lox), and alb-Cre; n = 9) and LIRKO (n = 4) mice were studied by the euglycemic, hyperinsulinemic clamp technique. Mice were infused with [U-13C6]-glucose for 90 min (basal) and then clamped using 2.5 mU human insulin/kg/min (insulin) with glucose maintained at ∼125 mg/dl. Hepatic glucose production during the clamp was determined by subtracting the glucose infusion rate from whole-body glucose appearance. (b) RNA was prepared from liver of 8-week-old, random-fed control (WT, IR(lox/lox), and alb-Cre), and LIRKO mice and was subjected to Northern blotting using probes specific for phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), liver pyruvate kinase (L-PK), and glucokinase (GK). Results are expressed as mean arbitrary phosphorimager units corrected for RNA loading by hybridization to a cyclophilin probe ± SEM from at least four animals per genotype. Increase in Blood Glucose Glucose Homeostasis is Maintained by Insulin and Glucagon Type 1 Diabetes Jakob Suckale, Michele Solimena. The insulin secretory granule as a signaling hub. Trends in Endocrinology & Metabolism. Volume 21 Issue 10 Pages 599-609 (October 2010)  Carbohydrate Meal Unger RH: Glucagon physiology and patho-physiology. N Engl J Med 285:443–449, 1971 Regulation of Glucagon in Response to Hypoglycemia and Hyperglycemia Glucagon Signaling in Liver Glucagon signals through G-Protein Coupled Receptor cAMP stimulates PKA which targets several proteins - inhibition of glycogen synthase - activation of glycogen phosphorylase - activates the transcription factor CREB and promotes gluconeogenesis Pyruvate and Lactate provide the building blocks for gluconeogenesis Lactate and muscle