0224 - Ketone Bodies and Cholesterol - RM Flashcards
What is the role of ketone bodies and how are they used?
They are a second source of metabolic fuel. They are used in:The brain (75% of fuel in starvation conditions - in the absence of glucose)The heart and renal cortex (prefer ketone bodies over fatty acids and glucose)Skeletal muscle (can adapt to almost any fuel).
What are the three types of ketone bodies? Which is/are most important
Beta-Hydroxy-butyrate, aceto-acetate, and acetone. The first two are the most important.
After (hepatic) synthesis, what is the fate of a ketone body?
It is highly soluble in aqueous solutions, and is easily transported to peripheral tissue, where it is degraded into acetyl-CoA and enters the TCA cycle.
Outline the process of Ketone body synthesis
Ketone bodies are synthesised in the mitochondria of hepatocytes. While low-level stimulus is constant, production is stimulated when OAA is diverted from the TCA cycle to gluconeogenesis (i.e. starvation conditions).1. Two acetyl-CoA are condensed, with THIOLASE acting as the enzyme, forming ACETO-ACETYL-CoA, and spinning off one CoA (thiol group).2. A third acetyl-CoA is added by HMG-CoA SYNTHASE, forming HMG-CoA, and spinning off another CoA. This step is a branch point for either ketone body or cholesterol synthase.3. An acetyl-CoA is removed (spun off) by HMG-CoA LYASE, forming ACETO-ACETATE. This is a ketone body itself.4. Aceto-acetate can be decarboxylated (CO2 removed) to form ACETONE. Or, it can be acted on by ß-HYDROXY-BUTYRATE-DEHYDROGENASE and NADH to form ß-HYDROXY-BUTYRATE.
Briefly outline Ketone body catabolism
Ketone body catabolism is almost exactly the reverse of synthesis, however it cannot occur in the liver, due to the need of keto-acyl-CoA transferase, which is only found in peripheral tissue.1. ß-Hydroxy-butyrate is acted on by ß-HYDROXY-BUTYRATE DEHYDROGENASE and NAD, producing ACETO ACETATE and NADH.2. Aceto Acetate is acted on by KETO-ACYL-CoA-TRANSFERASE in the presence of succinyl-CoA. It removes the CoA from succinyl-CoA, and attaches it to the aceto-acetate, forming ACETO-ACETYL-CoA. (This is the step that cannot occur in the liver).3. Aceto-acetyl-CoA undergoes thiolysis via THIOLASE, which adds an additional CoA (thiol) group, forming two Acetyl-CoA molecules that can enter the TCA cycle.
What are the key regulations for ketone body synthesis and catabolism?
Low levels of intermediates in TCA cycle, due to gluconeogenesis. Acetyl-CoA thus can’t be processed in TCA cycle and is redirected to KB synthesis.The liver is a producer and exporter of KB’s, NOT a user (requirement for keto-acyl-CoA transferase, which isn’t found in the liver).Other key enzymes - Thiolase, HMG-CoA synthase/lyase, ß-hydroxy-butyrate dehydrogenase.
What is Cholesterol? What is it used for?(He’d love you to draw it in exam)
Cholesterol is a 27-carbon compound composed primarily of carbon skeletons of acetyl-CoA. It is produced in the cytosol and ER of all cells, and around 25% of the 800mg daily total is synthesised in the liver. Most of the rest comes from the intestines, adrenal glands, and reproductive organs and is used for hormone production.Uses:1 - ‘polyfilla’ for cell membranes.2 - Hormone composition3 - Fat emulsification.
Why is cholesterol regulation important and how does it occur?
Cholesterol is valuable in small quantities for membrane structure, hormone composition and fat emulsification. However, if homeostasis breaks down, high levels can lead to obesity and cardiovascular disease - thus, regulation is critical.Regulation primarily revolves around both the amount and activity of HMG-CoA REDUCTASE (which is the committed step - otherwise production would go to ketone bodies). Ultimately, synthesis is inhibited by high levels of cholesterol, and low levels of energy. - Rate of synthesis is controlled by steroid response element - high levels of cholesterol slow activity of HMG-CoA Reductase.- Presence of mevalonate can reduce the formation of HMG-CoA reductase (through interfering with mRNA used to form it).- Cells destroy HMG-CoA reductase when there are high levels of protein (including lipoprotein) products.- cAMP kinase reduces HMG-CoA reductases’s activity when there is low [ATP] (thus high AMP).-Insulin stimulates HMG-CoA reductase, glucagon inhibits it.
How is cholesterol Synthesised?(The first step is the most important for us)
A very complex process, involving 4 main steps:1. Acetyl-CoA is converted to MEVALONATE in the cytosol. This step is identical to the first few steps of ketone body production (acetyl-CoA (+thiolase)->acetoacetyl-CoA (+HMG-CoA Synthase)->HMG-CoA), except that it occurs in the cytosol. HMG-CoA REDUCTASE (plus 2 NADPH) acts on HMG-CoA to form mevalonate. This is the committed and regulated step.2. Mevalonate uses ATP to form an activated ISOPRENOID.3. Six activated isoprenoids are condensed into SQUALENE, which is similar in structure to cholesterol, but with open rings.4. In the ER, the squalene rings are closed to form CHOLESTEROL.
What are the three uses of cholesterol and its derivatives?
Esterification - Cholesterol is converted to cholesteryl esters in the liver to increase hydrophobicity, and exported to peripheral tissues via lipoproteins (predominately LDL).Bile acids (‘polar cholesterol’) and salts - Cholic acid (cholesterol with carboxylic acid group attached) is synthesised in liver, stored in gall bladder, and released in bile. It is amphiphilitic, so can emulsify dietary lipids in the GI tract and ensure their absorbtion. Hydrophilic bile salts can be conjugated from bile acids (most commonly with addition of glycine or taurine), and can also assist with absorbing dietary lipids.Hormones - Many hormones are based on cholesterol (particularly sex hormones). They all share a cholesterol base, with very small structural differences providing massively different effects in the body.
