Overview of lipid biochemistry Flashcards
Most non-polar/hydrophobic lipids
triglyceride and cholesterol esters So non-polar that they typically exist away from water in a droplet within cells or in the center of lipoproteins circulating in plasma
Intermediate polarity lipids
phospholipids, cholesterol Located at the interface of lipid and aqueous in membranes or at the surface of lipoproteins
Most polar/hydrophilic lipids
non-esterified or free fatty acids move in aqueous environments complexed to protein
Structure of lipids
Fatty Acid Biosynthesis
(De novo lipogenesis) Things to think of: acetyl CoA carboxylase, fatty acid synthase, uses NADPH, lipoprotein lipase, malonyl CoA When glucose is present in the liver or adipose tissue in excess such as during the fed state following a large dietary carbohydrate load, it can go down glycolysis to pyruvate, enter the mitochondria and be converted to acetyl CoA which is then converted to citrate, leaves the mitochondria…. then be made into fatty acid. Occurs in cytoplasm. Liver: Acetyl CoA → Citrate → leaves mitochondria → Acetyl CoA → Malonyl CoA → Fatty Acid Adipose tissue: Fatty acid + glycerol → Triglyceride. Or it can be stored as VLDL.
β Oxidation
Think of: hormone sensitive lipase, carnitine palmitoyl transferase 1 (CPT1) When the body is in negative energy balance such as occurs during short-term fasting or during exercise, fat becomes an important alternative fuel for muscle and liver in an effort to preserve glucose for the brain. In addition, oxidation of fat during fasting provides the energy (ATP) which is needed to fuel gluconeogenesis. Occurs in mitochondria. Triglycerides in adipose tissue → Fatty acids → Acyl carnine → into mitochondria → Acetyl CoA
Ketogenesis
Think of: HMG CoA synthase If insulin is very low or absent and counter-regulatory hormones quite high, such as occurs during long-term fasting, the acetyl CoA produced by beta-oxidation in the liver can take an alternate route and become a ketone body. Ketones (3-hydroxybutyrate and acetoacetate) serve as an alternative fuel for the brain and other tissues in states of prolonged dietary “glucose insufficiency”. It is as though the body decides that continuing to break down muscle to provide substrate for gluconeogenesis is counter-productive and the brain begins to use an alternate fuel that comes from fat to preserve lean body mass. There are several common conditions where ketone body formation occurs: starvation, diabetic ketoacidosis and alcoholic ketoacidosis. The things that all 3 of these conditions have in common are 1. very low insulin levels, 2. high counter-regulatory hormones, 3. An abundant source of substrate: fatty acids in the case of fasting and diabetic ketoacidosis, and EtOH in the case of alcoholic ketoacidosis. This is because ketones will only be formed when the acetyl CoA produced by fatty acid metabolism (or ethanol metabolism) exceeds the capacity of the TCA cycle to metabolize it (ATP/ADP is high).
Lipoprotein pathways
Since the non polar lipids cholesterol, cholesterol esters, triglyceride and phospholipids do not dissolve in water, they must move through the blood in some other way. They move in particles called lipoproteins that contain apo-lipoproteins and lipids in varying amounts. As a result of the differences in composition, different lipoprotein particles vary in size and density. These differences in size and density form the basis of how they are classified. There are 3 lipoprotein pathways: 1. Dietary fat pathway / Chylomicron pathway: triglyceride rich (majority) + phospholipid (minority) particles deliver dietary fat to skeletal muscle and adipose tissue. 2. VLDL pathway: triglyceride derived from the liver is delivered to skeletal muscle and adipose tissue 3. HDL pathway: largely functions as a reservoir and transport system for a variety of lipids including cholesterol from the periphery to the liver.
Cholesterol Synthesis
Think of: HMG-CoA reductase, requires NADPH Cholesterol is an important component of cell membranes, is a precursor for steroid hormones and bile acids, but also is the lipid that accumulates in atherosclerotic plaque and causes atherosclerosis. Some cholesterol comes from the diet, but it can also be synthesized from acetyl CoA thru the formation of hydroxymethyl glutaryl CoA. Acetyl CoA (after it leaves mitochondria) → HMG CoA (HMG CoA Reductase) → Mevalonate → Cholesterol
Phospholipid synthesis
Think of: Cyclo-oxygenase 1 and 2 There are 4 classes of specialized lipids 1. Phospholipids that have a glycerol backbone and a PO4 group attached to one of the positions of the glycerol backbone. These lipids serve a number of important functions in cell membranes and lipoprotein particles especially and come in several classes depending on the side chains that are attached to the PO4 group. 2. Sphingolipids are built on a ceramide backbone. The backbone is unique because it is derived in part from an amino acid (serine), thus it contains a nitrogen atom. 3. Glycosphingolipids have a ceramide backbone, but also have sugar residues attached to the “head group”. 4. Made from arachidonic acid which can form either leukotrienes or prostaglandins/thromboxanes. These last lipids are important regulatory molecules in a number of cell types involved in inflammation. Cyclo-oxygenase 1 and 2 are the critical enzymes in this synthetic pathway. There are specific drugs that inhibit this enzyme that have modulating effects on inflammation (aspirin, COX inhibitors).
