Unit 3 Study Guide (Vazhaikkurichi Rajendran) PDF

Synthesis of Sphingosine, Ceramide, Sphingomyelin, and Glycosphingolipids 1.) Sphingosine Synthesis: Palmitoyl-CoA condensed with AA, serine, to form Sphinganine Palmitoyl-CoA + Serine → Sphinganine 2.)Ceramide Synthesis: Sphinganine rxts with a long chain fatty acid to form ceramid...

Synthesis of Sphingosine, Ceramide, Sphingomyelin, and Glycosphingolipids 1.) Sphingosine Synthesis: Palmitoyl-CoA condensed with AA, serine, to form Sphinganine Palmitoyl-CoA + Serine → Sphinganine 2.)Ceramide Synthesis: Sphinganine rxts with a long chain fatty acid to form ceramide Sphinganine + long chain fatty acid → Ceramide 3.)Sphingomyelin Synthesis: Ceramide rxts with phosphatidylcholine or phosphatidylethanolamine to form Sphingomyelin Ceramide + (phosphatidylcholine or phosphatidylethanolamine) → Sphingomyelin 3.)Galactocerebroside Synthesis: Ceramide rxts with UDP-galactose to form galactocerebroside Ceramide + UDP-Galactose → Galactocerebroside 3.)Glucocerebroside Synthesis: Ceramide rxts with UDP-glucose to form Glucocerebroside Ceramide + UDP-glucose → Glucocerebroside Sphingomyelin Metabolism -Sphingomyelin: the hydroxyl group of ceramide esterified to phosphate group of either phosphorylcholine of phosphorylethanolamine Sphingomyelin: insulates nerves and facilitates rapid transmission of nerve impulse Sphingomyelinase: degrades sphingomyelin Abnormal accumulation of sphingomyelin due to defective sphingomyelinase results in Niemann-Pick Syndrome Cerebrosides Metabolism -Monosaccharide is the head group in cerebrosides! -Glucocerebroside: Found in non-neuronal tissues 𝛽-Glucosidase degrades the glucocerebrosides Abnormal accumulation due to defective 𝛽-glucosidase results in Gaucher’s disease -Galactocerebroside: found in brain cell membrane 𝛽-galactosidase degrades the galactocerebrosides Abnormal accumulation due to defective 𝛽-galactosidase results in Krabbe’s disease Sulfatides: sulfated galactocerebrosides ^Arylsulfatase A degrades the sulfatide ^Sulfatide accumulation due to defective Arylsulfatase A resulting in Alzheimer’s and Parkinsons Ganglioside Metabolism -Gangliosides (GM2): Sphingolipids that possess oligosaccharide groups with one or more sialic acids residues 𝛽-Hexosaminidase degrades GM2 Abnormal accumulation due to defective 𝛽-hexosaminidase A results in Tay-Sachs disease Sphingolipids Storage Cholesterol -Isoprenoids: cholesterol and cholesterol-like compounds -Cholesterol: precursor for bile salts and steroid hormones (vital component of biological membrane) Cholesterols comes from diet (~400mg/day) and de novo synthesis (~900mg/day) Synthesis Takes place in the liver Cholesterol from LDL inhibits both cholesterol synthesis and LDL receptor synthesis Insufficient dietary cholesterol intake stimulates LDL receptor and HMGR synthesis Cholesterol Synthesis - All tissues can synthesize cholesterol, but most of the cholesterol is synthesized in the liver -Cholesterol synthesis occurs in 3 phases: Phase 1: Formation of HMG-CoA from Acetyl-CoA Phase 2: Conversion of HMG-CoA to squalene Phase 3: Conversion of squalene to cholesterol (Acetyl-CoA → HMG-CoA → Squalene → Cholesterol) Cholesterol Synthesis (Phase 1: Acetyl-CoA → HMG-CoA) Cholesterol Synthesis (Phase 2 and 3: HMG-CoA → squalene → Cholesterol) Cholesterol Homeostasis -Cholesterol plays critical roles in biological functions, but excess can be toxic -Blood cholesterol level must be maintained within normal limits (>200 mg/dl) -Cholesterol homeostasis occurs through intricate regulation of bile acid synthesis and cholesterol synthesis Cholesterol biosynthesis is accomplished by the regulation of HMG-CoA Reductase (HMGR) Regulation of Cholesterol Biosynthesis - Cholesterol biosynthesis is regulated through HMG-CoA reductase (HMGR) Cholesterol Modification of HMGR Covalent Modification: modification of HMGR activity by phosphorylation or dephosphorylation Glucagon and Epinephrine inhibit HGMR activity by activating phosphoprotein phosphatase PRO Insulin Activates HMGR activity by inhibiting cAMP production Genomic Modification of HMGR Steroid regulation of gene expression Covalent Regulation of HMGR -Covalent Modification: modification of HMGR activity by phosphorylation or dephosphorylation Glucagon and Epinephrine inhibit HGMR activity by activating phosphoprotein phosphatase PRO Insulin Activates HMGR activity by inhibiting cAMP production ^High cAMP level inhibits PP1 by phosphorylation Genomic Regulation of Cholesterol Biosynthesis -Sterol-mediated changes in gene expression is major feature of cholesterol homeostasis Membrane PRO named Sterol-Regulatory-Element Binding Protein-2 (SREBP2) present in ER is the predominant regulator of cholesterol homeostasis ^SREBP2: regulates LDL receptor expression and NADPH synthesis  ^Transcription factor on N-terminus SREBP2 is released with cholesterol levels is low Functional Units of SREBP2 -SREBP2 has: Transcription factor domain (TFD) Sterol-sensing domain (SSD) SSD has a binding site for Insulin-induced gene (Insig) Insig: retention protein which retains SREBP2 in ER Sterol-Mediated Gene Expression -High cholesterol keeps Insig bound to SSD -Low cholesterol releases Insig from SSD -SREBP/SCAP complex transferred from ER to Golgi Complex In Golgi, two proteases cleave at 2 sites and release active TFD from SREBP2 -TFD moves into nucleus TFD binds to sterol regulatory elements (SRE) of sterol related genes and stimulates mRNA synthesis Sterol-Regulation of HMGR Gene Expression -Low cellular cholesterol stimulates: Cholesterol biosynthesis (e.g. HGMR) expression LDL receptor gene expression NADPH synthesizing genes: ^Glucose-6-Phosphate Dehydrogenase (G-6-PD) ^6-phosphogluconate dehydrogenase ^ Malic enzyme (malate – pyruvate) Atherosclerosis -Atherosclerosis: Hardening and narrowing of heart artery due to plaque build up Macrophages has receptors similar to LDL receptors that binds and oxidizes LDL In the presence of high LDL, macrophages accumulate more LDL, which converts them into foam cells Foam cells stick to walls of blood vessels and promote plaque formation As the foam cells necrose, cholesterol crystals form in the plaques Atheromas (plages) can block blood flow and rupture vein High Cholesterol and Drug Therapy -High total cholesterol (VLDL, LDL, and HDL) combined with high LDL are strongly associated with CV disease. -Statins (Lipitor, Atorvastinin, Crestor): class of drug that lowers blood cholesterol by inhibiting HGMR Most of the cholesterol synthesized in the night. Thus statins are taken in the evening. Statins may interfere with ubiquinone (UQ) synthesis, the critical molecule in ETC. Thus, statin therapy may be accompanied by CoQ supplement. Lecture 31: Integration of Metabolism (Feeding-Fasting Cycle) Organs Sparing Metabolic Workload 1.) Gastrointestinal (GI) tract (Pancreas) 2.) Liver 3.) Muscle (Skeletal muscle and cardiac muscle) 4.) Adipose Tissue (fat) 5.) Brain 6.) Kidney Role of Gastrointestinal tract -Gastrointestinal (GI) Tract: mixes, digests, absorbs and propels food -Stomach: secretes the hormone ghrelin that stimulates appetite -Small Intestine: secretes the hormone peptide YY (PYY) that inhibits appetites -Pancreatic-𝛽-cells: secrete the hormone insulin that stimulates glucose absorption in muscle -Pancreatic-𝛼-cells: secrete the hormone glucagon that stimulates catabolism Role of Liver and Muscle -Liver: plays a key role in nutrient metabolism and regulates blood glucose levels. Also, plays detoxification role -Muscle: Skeletal muscle constitutes about 50% of the body mass and consumes a large portion of the generated energy Cardiac muscle: uses glucose in the fed state, uses fatty acids in the fasting state Insulin activates glucose absorption into skeletal and cardiac muscle through GLUT4 translocation Role of Adipose Tissue, Brain and Kidney - Adipose Tissue: Stores energy in the form of triglycerides Adipose tissue secretes leptin, a peptide hormone Leptin promotes satiety (inhibits appetite) -Brain: directs most metabolic processes Hypothalamus plays an important role in energy balance Uses 20% of the body’s energy resources -Kidney: maintains stable internal body environments. Filters the blood plasma, absorbs the nutrients and electrolytes, regulates the blood pH and maintains the body’s water content Feeding-Fasting Cycle -Despite the constant energy requirements, mammals consume food only intermittently Intermittent food intake is possible because of the mechanism for storing and mobilizing the energy-rich molecules derived from food -Mammals must have the metabolic integration and regulatory influence of hormones Substrate concentrations are also important factors in controlling the metabolism -Postprandial State: after a meal when nutrient levels are high -Post-absorptive State: state after an overnight fasting when nutrient levels are low Feeding Phase -In the postprandial state, Nutrients are absorbed in transported via portal blood to the liver - glucose movement from the intestine to the liver stimulates insulin release from pancreatic-𝛽-cells Insulin release triggers the glucose uptake, glycogenesis, fat synthesis and storage, and protein synthesis -Lipids are transported into lymph as chylomicrons Chylomicrons pass through the bloodstream and Supply fatty acids to muscle and adipose tissue Chylomicron remnants deliver the phospholipids, cholesterol, and remaining triglycerides to the liver - In the liver, the cholesterol is used to make bile acids and the fatty acids are used to synthesize phospholipids The lipids, phospholipids, cholesterol and proteins are packaged as VLDL for export to tissues Fasting Phase -Decreased blood glucose and insulin levels induced glucagon release from pancreatic-𝛼-cells Glucagon prevents hypoglycemia by stimulating glycogenolysis and gluconeogenesis in the liver -In the event of prolonged or overnight fasting, the blood glucose level is maintained by fatty acid mobilization Fatty acids are the alternative energy for muscle during prolonged fasting - muscles use fatty acids to conserve glucose for the brain and RBC. -Extraordinarily prolonged fasting (starvation) leads to metabolic changes to ensure adequate glucose availability for glucose requiring cells (brain and RBC) Fatty acids from adipose tissue and Ketone bodies from liver are mobilized - Glycogen depleted after 7 hours of fasting, so gluconeogenesis plays an important role Large amounts of amino acids from muscle protein are used for gluconeogenesis after several weeks of fasting brain adapts to use Ketone bodies as energy source Feeding Behavior -Regulating feeding Behavior involves hormone and neuronal signals as well as sensory input from the environment (The five senses) Both are integrated in the brain to regulate appetite -The first order neural circuits named arcuate nucleus (ARC) that control the appetite are present in the hypothalamus part of the brain -The ARC consists of two types of neurons:  Agouti-related protein (AgRP) and neuropeptide Y(NPY) containing neurons ^AgRP/NPY activation Stimulates appetite Pro-opiomelanocortin (POMC) peptide containing neuron ^POMC activation inhibits appetite Ghrelin stimulates food intake -The appetite inducing stomach hormone ghrelin activates AgRP/NPY neurons to increase food intake AgRP/NPY activation also inhibits POMC Leptin inhibits food intake -Leptin, insulin and PYY inhibits AgRP/NPY neurons to inhibit appetite and reduce food intake Leptin also activates POMC neurons to inhibit appetite and reduce food intake Diabetes Mellitus -Diabetes mellitus is a metabolic disease, 2 types: Type 1 diabetes Type 2 diabetes -In both type 1 and type 2 diabetes, the cells fail to acquire glucose from blood -In both diabetes the blood glucose level is high Hyperglycemia: high blood glucose Hypoglycemia: low blood glucose Type-1 Diabetes -Type 1 Diabetes: Also known as Juvenile diabetes insulin-dependent diabetes Autoimmune disease Caused as a result of destruction of pancreatic-Beta-cells Caused as a result of inadequate insulin -Symptom in Type-1/insulin-dependent diabetes resulting in ketoacidosis Feel thirsty, Frequent urination (polyurea) -Treatment for type-1/insulin dependent diabetes is insulin injection/infusion Type-2 Diabetes -Type 2 diabetes; Insulin-independent diabetes Caused by insulin-insensitivity of target cells -Treatment: Diet and exercise Prolonged uncontrolled type 2 diabetes will become insulin dependent Symptoms of Diabetes -Basic feature of diabetes is dysfunction of the fuel metabolism -Major diabetics symptoms are hyperglycemia, glucosuria and dyslipidemia -Hyperglycemia: high blood glucose level Acute symptom in both type 1 and type 2 diabetes -Glycosuria: Presence of glucose in the urine Leads to osmotic diuresis and polyuria (frequent urination, cause excessive thirst) -Dyslipidemia: Abnormal blood lipid and lipoprotein levels Obesity -Why are many humans predisposed to obesity in the modern world? Humans have gone from physically challenging hunter-gatherer and agrarian Lifestyles and to sedentary Lifestyles with easily available cheap, calorie-dense food ( fructose introduction into the diet, 1970’s) Mutation either in leptin or in leptin receptor also leads to obesity, as a result of overeating obesity is now recognized as a contributing factor in metabolic syndrome Metabolic Syndrome -Metabolic Syndrome: A cluster clinical disorders that include obesity, hypertension, dyslipidemia and Insulin resistant -Metabolic syndrome includes: Hyperinsulinemia (high blood insulin level) Decreased insulin- dependent glucose uptake and muscle excess glucose production via gluconeogenesis excess blood free fatty acids (FFA) which disrupt insulin sensitive signal transduction type 2 diabetes increased chance of vascular disease Body Mass Index (BMI) -BMI Measurement: BMI is a measure of a person’s body composition that is based on both weight (Kg) and height (m) BMI =