Week 4 Lecture 6 PDF

Week 4 Lecture 6  Eating meals that are rich in carbohydrates stimulates insulin secretion and activation of fatty acid synthesis. High carbohydrates promotes the production of citrate and the acetyl-Coa in the cytosol. ACC The enzyme acetyl-coa carboxylase (ACC)...

Week 4 Lecture 6  Eating meals that are rich in carbohydrates stimulates insulin secretion and activation of fatty acid synthesis. High carbohydrates promotes the production of citrate and the acetyl-Coa in the cytosol. ACC The enzyme acetyl-coa carboxylase (ACC) is the rate limiting step in fatty acid synthesis. ACC is inhibited when there is not enough energy. Just like a mobile electronic device, every living cell contains a “rechargeable battery” formed by pairs of interconvertible chemicals. The key chemicals within the cell are ATP and ADP, interconverted by the reaction ATP ↔ ADP + phosphate. This reaction is maintained by catabolism many orders of magnitude away from equilibrium, yielding a high ratio of ATP to ADP that is used to drive energy-requiring processes. In animal cells ATP is mainly generated via the mitochondrial ATP synthase, thus “charging the battery”. Almost every other function that cells perform requires energy, and most are driven by the hydrolysis of ATP back to ADP and phosphate, thus “discharging the battery”. Clearly, ATP generation needs to remain in balance with ATP consumption, and regulatory proteins that sense ATP and ADP levels would be a logical way to achieve this. However, all eukaryotic cells express high levels of adenylate kinase, and the reversible reaction it catalyzes (2ADP ↔ ATP + AMP) is usually maintained close to equilibrium. This means that any rise in the ADP:ATP ratio, which signifies falling energy status, causes the adenylate kinase reaction to be displaced towards ATP and AMP production. Thus, falling cellular energy is associated with increases not only in ADP, but also AMP. The relative increase in concentration is always much greater for AMP than ADP, although its absolute concentration remains lower than that of ADP unless energy stress becomes quite severe Acetyl-coa carboxylase (ACC) is inhibited by AMPK (AMP Kinase). AMPK phosphorylates ACC, which leads to inhibition, and decreasing activity of the rate limiting step in fatty acid synthesis. AMPK is inactive in the presence of insulin. When AMP/ADP ratio is high, AMPK is activated. What happens to the AMP/ATP ratio when glucose levels are high? Fatty acid synthesis starts with the formation of palmitic acid (C16) from acetyl-CoA and malonyl-CoA (which is itself a 3-carbon molecule formed from acetyl-CoA). Another difference between the catabolic and anabolic reactions for fatty acids is the location: whereas we saw that catabolism occurs largely in the mitochondria, fatty acid synthesis is run from a single large cytoplasmic enzyme complex. The fatty acid synthase system is comprised of seven enzymes linked together with an acyl carrier protein (ACP). This complex is found in the cytoplasm, so its substrates must be as well. The acetyl- CoA in the cytoplasm is primarily derived from the mitochondrial acetyl-CoA via a citrate-malate shuttle that couples deacetylation in the mitochondrion with acetylation in the cytosol. Eating meals that are rich in carbohydrates stimulates insulin secretion and activation of fatty acid synthesis. High carbohydrates promotes the production of citrate and the acetyl-Coa in the cytosol. The enzyme acetyl-coa carboxylase (ACC) is the rate limiting step in fatty acid synthesis.  Triglyceride Biosynthesis Acyl-CoA The acyl-CoA could be a fatty acid like palmitate. But in this case would be palmitoyl-CoA. GK: Glycerol Kinase GPAT: glycerol-3-phosphate acyl-transferase LPAAT: lysophosphatidic acid acyl-transferase PP: phosphotidic acid phosphohydrolase DGAT: diacylglycerol acyl-transferase Triglyceride Biosynthesis and Lipid Droplets  Lipid Droplets: Organelles for Lipid Storage Walther TC, Chung J, Farese RV Jr. Lipid Droplet Biogenesis. Annu Rev Cell Dev Biol. 2017 Oct 6;33:491-510. doi: 10.1146/annurev-cellbio-100616-060608. Epub 2017 Aug 9. PMID: 28793795; PMCID: PMC6986389.  Smooth and Rough Endoplasmic Reticulum Lipids (cholesterol esters and triglycerides) are synthesized in the smooth ER. Enzymes involved in triglyceride biosynthesis are found in the ER. Lipid droplets will bud from the ER and form separate organelles that where lipids can be stored for the long-term. DGAT enzymes catalyze the final step in triglyceride synthesis in the ER. ACAT enzymes that make cholesterol esters are found in the ER and the cholesterol esters can be stored in lipid droplets. Walther TC, Chung J, Farese RV Jr. Lipid Droplet Biogenesis. Annu Rev Cell Dev Biol. 2017 Oct 6;33:491-510. doi: 10.1146/annurev-cellbio-100616-060608. Epub 2017 Aug 9. PMID: 28793795; PMCID: PMC6986389.  Triglyceride Biosynthesis and Lipid Droplets Step 1: Triacylglycerol Synthesis Within the ER In eukaryotes, neutral lipids (neutral lipids don’t have a charge and they are not soluble in water), such as triglycerides or cholesterol esters, are synthesized predominantly in the ER. TGs were discovered in the early 1800s. It was not until approximately 1960 that the biochemical reactions yielding TGs were discovered by Kennedy and coworkers. This pathway, termed the de novo glycerolipid synthesis pathway, or the Kennedy pathway, is the primary pathway of TG synthesis in most cells. It uses glycerolphosphate and fatty acyl-CoA to generate glycerolipids, such as glycerophospholipids or TGs. A second pathway for TG synthesis, the monoacylglycerol pathway, exists in some cell types, such as intestinal enterocytes and adipocytes, and is involved in the recycling of mono- acylglycerols and diacylglycerols, generated by TG hydrolysis, back to TGs via a reesterification process. The monoacylglycerol acyltransferase (MGAT) enzymes 1–3 play key roles in this pathway. Walther TC, Chung J, Farese RV Jr. Lipid Droplet Biogenesis. Annu Rev Cell Dev Biol. 2017 Oct 6;33:491-510. doi: 10.1146/annurev-cellbio-100616-060608. Epub 2017 Aug 9. PMID: 28793795; PMCID: PMC6986389. Triglyceride Biosynthesis and Lipid Droplets Histological analysis of the Liver shows lipid droplets of varying sizes A haematoxylin and eosin-stained tissue sample from a human showing hepatocytes exhibiting microvesicular (arrowheads) and macrovesicular (arrows) steatosis. Hepatocytes with microvesicular steatosis have abnormal accumulation of lipid with preserved cellular architecture, including a non-displaced nucleus, whereas hepatocytes with macrovesicular steatosis have one large droplet that displaces the nucleus.  Dietary Carbohydrate Increases VLDL Production Plasma Dietary Triglyceride Carbohydrate (VLDL) Insulin Glucose Homeostasis is Maintained by Insulin and Glucagon  Glycogen is stored as granules in the cell. Glycogen granules increase and decrease in size depending on the nutritional state of the organism. During the fed state, these glycogen granules grow, a process that is regulated by insulin. While in the fasting state these glycogen granules shrink in response to glucagon. In the liver glycogen provides a source of glucose for gluconeogenesis and in the muscle glycogen provides a source of energy for internal ATP synthesis. Transmission electron micrograph (TEM) of glycogen in a liver cell of the salamander Batrachoseps attennuatus. The black dots are glycogen, scatt- ered among several mitochondria (oval bodies) & the tubular network of endoplasmic reticulum  What would be the clinical manifestation of deletion of Glucose-6-phosphatase? Transmission electron micrograph (TEM) of glycogen in a liver cell of the salamander Batrachoseps attennuatus. The black dots are glycogen, scatt- ered among several mitochondria (oval bodies) & the tubular network of endoplasmic reticulum https://www.chp.edu/our- services/rare-disease- therapy/patient-stories/joshua- elm Patients with GSD I typically present in the first few months of life with severe fasting hypoglycemia within 3–4 hours after a feed. There is an associated lactic acidosis and hyperuricemia that is typically not seen in other GSDs. Blood ß-hydroxybutyrate (ß-OHB) levels increase only modestly in GSD I as it is considered a hypoketotic hypoglycemic state.