Medical Biochemistry II: Fatty Acid Regulation PDF

Medical Biochemistry II Fatty Acid Regulation Student Learning Outcomes: 1 Describe the regulation of FA synthesis 2 3 4 Describe the Triacylglycerol cycle and its regulation Describe the impact of triacylglycerol in diabetes patients Describe regulation of FA release in adipocyte by glyceroneogenes...

Medical Biochemistry II Fatty Acid Regulation Student Learning Outcomes: 1 Describe the regulation of FA synthesis 2 3 4 Describe the Triacylglycerol cycle and its regulation Describe the impact of triacylglycerol in diabetes patients Describe regulation of FA release in adipocyte by glyceroneogenesis 5 Explain the hormones released by adipose tissue and their functions Regulation of FA synthesis Acetyl-CoA carboxylase is rate limiting step Palmitoyl-CoA is neg regulator of carboxylase Citrate is positive regulator of carboxylase Regulation of Triacylglycerol cycle Triacylglycerol cycle between liver and adipose tissue is controlled by activity of PEP carboxykinase PEP carboxykinase limits the rate of both gluconeogenesis and glyceroneogenesis Regulation of Triacylglycerol cycle Glucocorticoid hormones (cortisol) regulate PEP carboxykinase reciprocally in the liver and adipose tissue Liver é both gluconeogenesis and glyceroneogenesis In adipose ê glyceroneogenesis Result: é both blood glucose and blood FA In type II diabetes Class of drugs called thiazolidinediones bind to receptor on adipose tissue (proliferatoractivated receptor γ) Binding this receptor activates PEP carboxykinase Increases production of TAGs in adipose Result: ê blood FA; muscle cells take up glucose as fuel source Fasting releases FA from Adipose tissues Insulin low, glucagon high; cAMP → PKA…. Active Hormone Sensitive Lipase-P is TAG lipase Hormone sensitive lipase cleaves FA from TAG FA travel in blood bound to serum albumin Muscle oxidizes FA for energy Liver makes ketone bodies from Acetyl CoA Liver uses glycerol for gluconeogenesis Fig. 23 Regulation of FA release by adipocytes via glyceroneogenesis As adipocyte is stimulated to release FA’s the FA’s can also be re-esterified and prevented from releasing. Thought to have a role in controlling FA release from adipose tissue Regulation of FA release by adipocytes via glyceroneogenesis 40% of the FA will be re-esterified by glycerol 3-phosphate back to TAGS Key enzyme is phosphoenolpyruvate carboxykinase (PEPCK) PEPCK is induced following activation of PKA (remember PKA is activated following glucagon) via cAMP other Adipocytes can also make hormones: Leptin – identified as helping ob/ob obese mice lose weight Binds JAK receptor/ signals through sTAT Leptin is released as TAG levels increase Leptin binds receptors in hypothalamus Hypothalamus release neuropeptides that signal a cessation of eating Givein leptin to leptin deficient patients will result is weight loss Giving leptin to obese patients does not have same effect Though to be due to insensitivity of leptin receptors due to overstimulation of receptors in obese patients other Adipocytes can also make hormones: Adiponectin – maybe linked to insulin resistance Release from adipose tissue decreases as size of adipocytecyte gets larger Binds to two receptors AdipoR1 and AdipoR2 Binding initiates signal transduction and activation of AMPkinase (AMPK) and activation of PPARa (peroxisome proliferator-activated receptor alpha) Both lead to increase in FA oxidization in the muscle and liver Key concepts Fatty acids synthesized mainly in liver, from glucose Glucose to pyruvate in mitochondrion, forms Ac CoA, OAA, which form citrate Citrate in cytosol then to Ac CoA, malonyl CoA Fatty acid synthesis involve series 2-C additions from malonyl CoA to the w-C of Ac CoA onto FA synthase. Costs 2 NADPH and 1 ATP per cycle addition Fatty acids packaged as TG in liver as VLDL with proteins and other lipids; digested by LPL on capillaries and FA enter cells (oxidized or stored) Glycerophospholipids similar synthesis Spingolipids from sphingosine (serine + FA)