Week 3 Lecture 5 PDF

Week 3 Lecture 5 Objectives Understand how glucose and fructose metabolism are different. Learn about the impact of fructose and glucose on metabolic parameters. Understand how triglycerides are synthesized. Learn how glucose contributes to fatty acid synthesis. Learn about...

Week 3 Lecture 5 Objectives Understand how glucose and fructose metabolism are different. Learn about the impact of fructose and glucose on metabolic parameters. Understand how triglycerides are synthesized. Learn how glucose contributes to fatty acid synthesis. Learn about the type of fatty acids that can be made and which are dietary. Learn about LXR and SREBP1c and their role in fatty acid synthesis. Consumes 2 ATP and generates 4 ATP, for a net production of 2 ATP. Also generates 2 NADH from NAD+. This process does not require oxygen. Where is oxygen consumed? Oxygen is the final electron acceptor in the electron transport chain, which allows for oxidative phosphorylation. Without oxygen, the electrons will be backed up, eventually causing the electron transport chain to halt. What are two possible fates of pyruvate? Fructose vs Glucose Fructose is sweeter than glucose, so it's most often used as an added sugar in processed foods, whether in the form of high- fructose corn syrup or just plain old sugar. Though both sugars promote fat build-up in the liver, the liver metabolizes fructose and glucose differently. What kind of experiment would you do to test whether glucose or fructose increases risk for obesity of metabolic risk?  GLUCOS VS FRUCTOSE: What’s the evidence? Combination of High-fat diet with fructose shows greater weight gain in mice when compared to mice eating a high-fat diet supplemented with glucose. (A) Weight gain of mice on chow and HFD, supplemented with either regular, 30% fructose, or glucose-sweetened water for 10 weeks.  GLUCOS VS FRUCTOSE: What’s the evidence? Combination of High-fat diet with fructose shows greater increase in adipose tissue size in mice when compared to mice eating a high-fat diet supplemented with glucose. (C) Percentage of visceral fat/ total fat as measured by DEXA scan after 8 weeks on diet. Utilization of fructose and glucose in the liver. Hepatic fructose metabolism begins with phosphorylation by fructokinase (EC 2.7.1.4). Fructose carbon enters the glycolytic pathway at the triose phosphate level (dihydroxyacetone phosphate and glyceraldehyde-3- phosphate). Thus, fructose bypasses the major control point by which glucose carbon enters glycolysis (phosphofructokinase; EC 2.7.1.11), where glucose metabolism is limited by feedback inhibition by citrate and ATP. This allows fructose to serve as an unregulated source of both glycerol-3- phosphate and acetyl-CoA for hepatic lipogenesis. P, phosphate. Lipid Synthesis can be described in 3 steps: 1)Biosynthesis of glycerol 2)Biosynthesis of fatty acids 3)Biosynthesis of triacylglycerol Role of glycolysis in making glycerol-3-phosphate Role of glycolysis in making glycerol-3-phosphate Glycerol-3-phosphate required for triglyceride biosynthesis. In adipocytes glycerol-3-phosphate is converted to glycerol, which can then exit the cell and go into the blood stream.  Except for the essential fatty acids linoleic acid and -linolenic acid, most human cells are capable of synthesizing fatty acids from acetyl-CoA. The major sites of synthesis are the liver, lungs, adipose tissue, lactating ACS mammary glands, brain, and kidneys. ACC  Nearly all acetyl-CoA needed for fatty acid synthesis is produced in the mitochondrial matrix. It is formed there from the oxidation of pyruvate, which may arise from the oxidation of glucose and fructose (and ACS possibly fatty acids), and from the ACC degradation of the carbon skeletons of some amino acids.  Carbons from glucose can become the building blocks for making new fatty acids. Fatty acids can be made through de novo lipogenesis (AKA…fatty acid synthesis) or imported through a plasma membrane ACS transporter. ACC Pyruvate Kinase is regulated by gene expression and phosphorylation. Produces the pyruvate that enters the mitochondria. In the TCA cycle, citrate can be exported into the cytosol. The enzyme ACLY (ATP Citrate Lyase converts citrate to acetyl-CoA and ACC (acetyl-CoA carboxylase) converts acetyl- CoA to Malonyl-CoA.  Malonyl-CoA and Acetyl-CoA are joined through several consecutive steps to generate the long-chain fatty acid palmitate ACS (16:0). ACC Fatty acids need to be modified to include coenzyme A in order to be esterified. Esterified means that an ester bond is generated. Joining fatty acids to a glycerol molecule requires esterification. The production of triacylglycerol (AKA triglycerides) requires fatty acids to have Coenzyme A attached.  Majority of fat synthesis occurs in the liver, brain, and adipose tissue. Although many cells types have the ability to synthesize ACS fatty acids with a lower capacity. ACC  Majority of fat synthesis occurs in the liver, brain, and adipose tissue. Although many cells types have the ability to synthesize ACS fatty acids with a lower capacity. ACC  Lipid Structure Lipids are esters of fatty acids joined by glycerol called triglycerides. When a fatty acid has no double bonds, it is known as a saturated fatty acid because no more hydrogen may be added to the carbon atoms of the chain. A fat may contain similar or different fatty acids attached to glycerol. Long straight fatty acids with single bonds tend to get packed tightly and are solid at room temperature. Animal fats with stearic acid and palmitic acid (common in meat) and the fat with butyric acid (common in butter) are examples of saturated fats. Mammals store fats in specialized cells called adipocytes, where globules of fat occupy most of the cell’s volume. In plants, fat or oil is stored in many seeds and is used as a source of energy during seedling development. Unsaturated fats or oils are usually of plant origin and contain cis unsaturated fatty acids. Cis and trans indicate the configuration of the molecule around the double bond. If hydrogens are present in the same plane, it is referred to as a cis fat; if the hydrogen atoms are on two different planes, it is referred to as a trans fat. The cis double bond causes a bend or a “kink” that prevents the fatty acids from packing tightly, keeping them liquid at room temperature  Omega Fatty Acids Essential fatty acids are fatty acids required but not synthesized by the human body. Consequently, they have to be supplemented through ingestion via the diet. Omega-3 fatty acids (like that shown in this figure fall into this category and are one of only two known for humans (the other being omega-6 fatty acid). These are polyunsaturated fatty acids and are called omega-3 because the third carbon from the end of the hydrocarbon chain is connected to its neighboring carbon by a double bond. Alpha-linolenic acid is an example of an omega-3 fatty acid. It has three cis double bonds and, as a result, a curved shape. For clarity, the carbons are not shown. Each singly bonded carbon has two hydrogens associated with it, also not shown. Triglyceride Biosynthesis 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  Dietary Carbohydrate Increases VLDL Production Plasma Dietary Triglyceride Carbohydrate (VLDL) Insulin