Week 4 Lecture 7 v2 PDF

Week 4 Lecture 7 Explain why a patient with glycogen storage disease type 1 would have hyperuricemia? Explain why a patient with glycogen storage disease type 1 would have hyperlipdemia? Explain why a patient with glycogen storage disease type 1 would have hyperlactatemia? Explain why a patient...

Week 4 Lecture 7 Explain why a patient with glycogen storage disease type 1 would have hyperuricemia? Explain why a patient with glycogen storage disease type 1 would have hyperlipdemia? Explain why a patient with glycogen storage disease type 1 would have hyperlactatemia? Explain why a patient with glycogen storage disease type 1 would have hyperlactatemia? How would fat oxidation in patients with glycogen storage disease type 1 be affected? Pompe disease is a multisystemic metabolic disorder caused by a deficiency of lysosomal acid alpha- glucosidase (GAA) leading to progressive accumulation of lysosomal glycogen, lysosomal swelling and rupture in all tissues of the human body Lysosomal acid alpha-glucosidase (GAA) is an enzyme responsible for the breakdown of glycogen in the lysosome. The accumulation of glycogen leads to impaired lysosomal function that can lead to irreversible damage. The inability to properly breakdown proteins and lipids in the lysosome can lead to detrimental outcome for the cell. Lysosome  Insulin signaling promotes the expression of SREBP1c in the liver. Insulin stimulates the insulin receptor, leading to a signaling cascade that promotes activation of mTORC1. mTORC1 is activated in the presence of nutrients. When SREBP1c is activated, it undergoes processing and cleavage in the golgi. Processed SREBP1c is translocated to the nucleus where in bind to sterol regulatory elements (SRE). DNA motif that SREBP binds to. Promotes fatty acid synthesis. Effects of insulin on Sterol regulatory element binding transcription protein (SREBP)-1c activation in liver. Signaling via Akt increases SREBF1 transcripts encoding SREBP-1c, activates the mammalian target of rapamycin complex 1 (mTORC1) pathway and inhibits Insulin-induced gene 2 (INSIG2) expression and degradation of nuclear (n)SREBP-1c by phosphorylation of Glycogen synthase kinase 3 (GSK3). Transcriptional activation of the SREBP-1 promoter requires Liver X receptor (LXR). mTORC1 increases SREBF1 transcript levels, activates S6 kinase (S6K) and inhibits Lipin-1, a negative regulator of nSREBP-1c. Feedback inhibition of insulin signal transduction by mTORC1 is also shown. PAS-domain- containing serine/threonine-protein kinase (PASK) activation of SREBP maturation occurs downstream of mTORC1 or in a parallel pathway. Activation and inhibition are shown by black arrows or dotted red lines, respectively. Abbreviations: bHLH, basic helix-loop- helix; Reg, regulatory domain; WD, WD40 domains  Western blot analysis of liver from WT(wild-type) and obese (ob) mice. SREBP1c expression is elevated in the liver of obese mice. Obese mice develop fatty liver and accumulate excess triglycerides. This observation is a correlation. How can we support causation? Design and experiment to test the hypothesis that SREBP1 promotes fatty liver.  Figure 2. Macroscopic comparison of livers from C57Bl6 and alb-SREBP-1c mice. Knebel B, Haas J, Hartwig S, Jacob S, Köllmer C, et al. (2012) Liver-Specific Expression of Transcriptionally Active SREBP-1c Is Associated with Fatty Liver and Increased Visceral Fat Mass. PLOS ONE 7(2): e31812. https://doi.org/10.1371/journal.pone.0031812 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031812 Northern blot of livers from wild-type and obese mice. You find that expression of SREBP1 and genes involved in fatty acid synthesis are elevated in obese mice. Because SREBP1 is a transcription factor you would like to test the hypothesis that SREBP1 promotes expression of these genes. Design an experiment to help you address this hypothesis. Northern blot of livers from wild-type and transgenic mice overexpressing SREBP1. What is the interpretation of this result?