Week 7 Lecture 12 PDF

Week 7 Lecture 12 Discuss the pathways that promote lipid utilization during the fasting state. A) Hormonal B) Substrate C) Organelles D) Key enzymes E) Signaling molecules Adipose Tissue Lipolysis Sepsis is associated with the development of an anorectic response since patients are often unwill...

Week 7 Lecture 12 Discuss the pathways that promote lipid utilization during the fasting state. A) Hormonal B) Substrate C) Organelles D) Key enzymes E) Signaling molecules Adipose Tissue Lipolysis Sepsis is associated with the development of an anorectic response since patients are often unwilling or unable to eat. During a normal starvation response and during sepsis, lipolysis in white and brown adipose tissue is being upregulated by several pro- lipolytic signals. The inhibitory effect on lipolysis of insulin, which is upregulated in sepsis due to high glucose levels, is however absent due to insulin resistance. Free fatty acids (FFAs) in the blood are upregulated in both conditions and can be taken up by peripheral organs to produce energy. The increased FFA levels activate and upregulate the expression of PPAR-α, the main transcription factor responsible for the induction of genes involved in the β- oxidation of fatty acids and the production of ketone bodies (KBs). During sepsis, PPAR-α levels are downregulated and the breakdown of fatty acids through β- oxidation is compromised, causing FFAs to accumulate in organs such as the liver, heart, and kidney, but also in the blood. Overall, the deficits in FFA breakdown during sepsis cause a shortage of energy and lipotoxicity and mitochondrial damage due to FFA accumulation. Green represents the normal starvation response, and red represents the response during sepsis. 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) A major function of the peroxisome is the breakdown of very long chain fatty acids through beta oxidation. In animal cells, the long fatty acids are converted to medium chain fatty acids, which are subsequently shuttled to mitochondria where they eventually are broken down to carbon dioxide and water. In yeast and plant cells, this process is carried out exclusively in peroxisomes. Peroxisomes (microbodies) were first described by a Swedish doctoral student, J. Rhodin in 1954. They were identified as organelles by the Belgian cytologist Christian de Duve in 1967. De Duve and co-workers discovered that peroxisomes contain several oxidases involved in the production of hydrogen peroxide (H 2O2) as well as catalase involved in the decomposition of H2O2 to oxygen and water. Due to their role in peroxide metabolism, De Duve named them “peroxisomes”, replacing the formerly used morphological term “microbodies”. Later, it was described that firefly luciferase is targeted to peroxisomes in mammalian cells, allowing the discovery of the import targeting signal for peroxisomes, and triggering many advances in the peroxisome biogenesis field. 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.[citation needed]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- Characteristic facial abnormalities in a neonatal affected by phospholipids that are especially important for brain and peroxisomal disorders. Peroxisomal disorders are associated lung function. with characteristic facial abnormalities (high forehead, frontal bossing, small face, low set ears, slanted eyes, etc.). Patients present as floppy children, due to their decreased muscle tone (hypotonia). Developmental delay and mental retardation is common to all patients, and vision and hearing are affected 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.  All Reactions Occur Between α and β Carbons β-carbon α-carbon Fatty Acid Metabolism Fatty Acid Oxidation - Beta Oxidation Enzymes in Mitochondria and Peroxisomes Generates More ATP Per Carbon Than Sugars Proceeds 2 Carbons at a Time α β Fatty Acid Metabolism Preparation for Oxidation Before Oxidation, Fatty Acids Must be Activated and Transported to the Mitochondrion. Activation Begins in the Cytoplasm Long Chain Fatty Acyl-CoA Ligase Fatty Acid Fatty Acyl-CoA Four Steps in Fatty Acid Oxidation Fatty Acid Metabolism Beta Oxidation - Reaction 1 Oxidation Creates Trans Intermediate Unrelated to Trans fat Three forms of Enzyme Medium Form Problem in SIDS Used to Generate ATP in Oxidative Phosphorylation β α Fatty Acid Metabolism Beta Oxidation Reaction 2 Similar to Fumarase Reaction of Citric Acid Cycle Preparation for Next Oxidation Step β β α α Fatty Acid Metabolism Beta Oxidation Reaction 3 Similar to Malate Dehydrogenase Reaction of Citric Acid Cycle Used to Generate ATP in Oxidative Phosphorylation β β α α Fatty Acid Metabolism Beta Oxidation Reaction 4 Thiolase Enzyme Catalyzes the Reverse Reaction When the R-Group is a Hydrogen Oxidized in Citric Acid Cycle β α Shortened by 2 Carbons Fatty Acid Metabolism Fatty Acid Oxidation - Summary In Summary - Each Round of Oxidation Creates One FADH2, One NADH, one Acetyl-CoA, and a Fatty Acid Shortened by Two Carbons Each Acetyl-CoA Released in Matrix of Mitochondrion Where it is Readily Oxidized in the Citric Acid Cycle.