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Flashcards in Lipid synthesis and metabolism Deck (85)
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61

Describe how the body uses ketone bodies (essentially, why does the body risk the ketoacidosis)?

• Acetoacetate and Beta-hydroxybutarate are water-soluble transportable forms of acetyl units
• The liver does not use ketone bodies itself as an energy source, bu tmany other tissues do
• In fact, they are the primary fuel choice for cardiac muscle and the renal cortex
• 3-hydroxybutarate is oxidized to acetoacetate by 3-hydroxy butyrate dehydrogenase, and this produces NADH
• Acetoacetate is then provided with a CoA taken from succinyl CoA by thiophorase
○ The product acetoacetyl CoA can be converted into two acetyl CoAs
• The liver does not have thiophorase
• So essentially the liver is generating these acyl groups that are easily transportable to give other tissues another source of acetyl CoA for the TCA cycle to continue

62

What is the normal concentration of ketone bodies in the blood and in the urine of a normal person (as opposed to diabetic)?

• Normal urinary secretion
○ Less than 125 mg/24hr period
• Diabetic urinary secretion
○ Up to 5,000mg/24 hr period
• Blood concentration normal
○ Less than 3mg/100mL
• Diabetic blood concentration
○ 90mg/100mL

63

What is the main enzyme that is super active in DKA?

• Hormone sensitive lipase! We have essentially no insulin activity and tons of glucagon secretion and activity
• Thus there is large amounts of fatty acid release from adipose
• Fatty acid oxidation leads to high levels of NADH which inhibits the TCA cycle and forces excess acetyl CoA into the ketone body synthesis pathway
• More ketone bodies in the blood (acetoacetate and 3-hydroxybutyrate) means acidosis

64

In what two forms does cholesterol appear in the body?

• Free cholesterol
• Cholesterol esters

65

What are the sources of cholesterol?

• Dietary and de novo synthesis
• Dietary -
○ We consume about 600mg of cholesterol each day and 1/2 of which is absorbed
○ Meat, eggs, whole dairy products
○ Other half is stool excreted
• Synthesis -
○ We synthesize about 1g of cholesterol each day
○ Normally under tight regulation (mostly hepatocyte driven)
○ So we actually make more than we eat
○ The liver is the major site of cholesterol synthesis
○ Adrenal cortex, ovaries and testes also make cholesterol for steroid hormones
• Bile salts
○ About what we each each day is put into bile salts
○ Enterohepatic circulation keeps them in the body

66

There are two isoforms of HMG CoA synthase in the hepatocyte. What do each of these isoforms do and where are they?

• They are either in the cytoplasm or the mitochondria
• Cytosolic isoform - cholesterol synthesis
• Mitochondrial isoform - ketone body synthesis or ketogenesis

67

Describe the three general steps in cholesterol biosynthesis


• First step -
○ Synthesis of HMG CoA from acetyl CoA
○ Similar to the synthesis of ketones and is catalyzed by thiolase and HMG CoA synthase
○ 2 isoforms of this enzyme in the hepatocyte
○ Cytosolic isoform participates in cholesterol synthesis
○ Mitochondrial version participates in ketone generation
• Second step -
○ Conversion of HMG CoA to mevalonate by HMG CoA reductase
○ RATE LIMITING STEP in the syntheiss pathway
○ KEY REGULATED STEP in the synthesis pathway
○ Cytosolic reaction and USES NADPH as the reducing agent
• Third "phase" -
○ Series of reactions to convert mevalonate to cholesterol
○ First converted to two activated isoprenes (isopentyl pyrophosphate)
○ Intermediat stage including geranyl phyrophosphate and farnesyl phyrophosphate
○ 2 molecules of farnesyl pyrophosphate combine to form squalene
○ Ring closure - squalene is turned into four-ring steroid structure, first as lanosterol then cholesterol

68

There are 5 given things that are important to remember. What are these?

• 1 - where the pathway occurs (cytoplasm)
• 2 - synthesis STARTS with acetyl CoA
• 3 - NADPH is the source of energy (reducing agent) for the synthetic pathway
• 4 - the key regulated step is HMG-CoA reductase
• 5 - the names of key intermediates (geranyl pyrophosphate, farnesyl pyrophosphate, isopentyl pyrophosphate, squalene, lanosterol)

69

In what step of cholesterol synthesis is energy used?

• ATP is used (3) in the conversion of mevalonate into isopentenyl pyrophosphate
• NADPH (2) is used by HMG-CoA reductase in the conversion of HMG-CoA into mevalonate
*NADPH (2) is used in the reduction of squalene into the ring form of linosterol and cholesterol

70

What "other fates" besides cholesterol synthesis are geranyl pyrophosphate and farnesyl pyrophosphate destined for?

• Prenylated proteins
• Heme a
• Dolichol
• ubiquinone

71

What three pathways contribute to the intracellular cholesterol content in hepatocytes

• Intracellular synthesis
• Uptake of lipoprotein cholesterol from LDL and to a lesser extent HDL particles
• Enterohepatic circulation of bile acids
○ Bile acids are made up by cholesterol, are secreted and are taken back up in the small intestine (distal ileum)

72

The key regulated step in cholesterol synthesis is what? And what are the regulating molecules/processes?

• HMG CoA reductase is the key regulated enzyme and the key regulated step in cholesterol biosynthesis (de novo)
• Transcriptional regulation
• Translational regulation
• Degradation of key enzyme
• Phosphorylation of key enzyme

73

Describe the transcriptional regulation of cholesterol synthesis




• When cholesterol is present in excess, HMG-CoA reductase gene is transcribed at a dramatically reduced rate
• Transcriptional control is the result of the actions of the transcription factor Sterol Regulatory Element Binding Protein
○ SREBP - super important to recognize
• When cholesterol levels are high in the hepatocyte, SREBP is retained in the golgi through binding to another protein, SCAP
• In this situation there is no stimulation of HMG-CoA reductase transcription
• When cholesterol levels are high, SREBP is released and can move to the nucleus to stimulate transcription of HMG-CoA reductase
• Insulin and glucagon regulate HMG-CoA reductase via transcription
• Insulin increases the expression of this enzyme
○ NADPH is high and acetyl CoA is present for the start of the synthesis pathway
• Glucagon decreases expression

74

How do statins work in general?

• They are analogs to mevalonate and thus competitively interfere with HMG-CoA reductase function
• Essentially a statin will drastically reduce or shut off the de novo synthesis of cholesterol
• Since we have about 1g of de novo synthesis, and about 1/2 that dietary intake, this goes a long way to lowering cholesterol in the body
○ Successful medication in preventing coronary artery disease CAD

75

Describe how the phosphorylation state of HMG-CoA reductase contributes to regulation of this key enzyme in the biosynthesis of cholesterol

• AMP kinase phosphorylates HMG-CoA reductase which inactivates the enzyme
• Phosph - deactive
• Dephosph - active

76

Describe the regulation of HMG-CoA reductase at the level of protein degradation

• When cholesterol is present in excess in the hepatocyte, the 1/2 life of HMG-CoA reductase decreases from 11 hrs to 2 hours
○ Targeted to the proteosome

77

Describe the translational regulation of HMG-CoA reductase

• When cholesterol is present in excess, the translation rate of the mRNA encoding HMG-CoA reductase is much less than in the absence of cholesterol
• The mRNA half-life decreases with excess cholesterol

78

What is meant by "complex lipids"?

• The varied and diverse class of lipids that have all sorts of diverse functions and relatively complex structures
• Know these well enough to know what buckets they fall in and associate them with key functions
• Triacylglycerols
○ Neutral storage lipids
• Phospholipids
○ Glycerophospholipids
○ Sphingolipids
§ Ceramide
• Glycolipids
○ Sphingosine backbone with a mono or oligosaccharide attached to it

79

Describe the general architecture of the lipid

• Backbone of either glycerol or ceremide
• Polar head group either a phosphate linked to alcohol
○ Glycerophospholipid
• Or phosphate linked to choline
○ Sphyngomyelin
• Or phosphate linked to a sugar moiety
○ glycosphyngolipid

80

What are the important things to remember about phosphatidylcholine?

• Along with PE, it is the most abundant phospholipid in the body
• Main component of lung surfactant
• Serves as a reservoir of choline
• Present in bile acids

81

What is the importance of phosphatidylserine?

• Also important for membrane synthesis
• Mostly synthesized by base exchange reaction

82

What are the important points of phosphatidylinositol?

• Important in signal transduction
○ IP3 and DAG and calcium release into the cell from ER stores
• Serves as a reservoir for arachidonic acid which is used in prostaglandin synthesis
• Important in membrane protein anchoring

83

What are the important points of sphingomyelin?

• Has a sphingosine/ceramide backbone
○ Not glycerol
• Has a choline headgroup
• Major structural lipid in NERVE tissue
• Precursor to this lipid is ceramide made from a fatty acid and an amino acid
○ serine

84

What are important things to remember in glycolipids or glycosphingolipids

• They have a ceramide or sphingosine backbone
○ Instead of phosphate + alcohol head group though they have a sugar headgroup
• UDP glucose or UDP galactose are the sugars added to the head groups
• Most important examples
○ Cerebroside
○ Globoside
○ Gangliosides
• Breakdown disorders here are classic STEP questions and can lead to multisystem problems

85

What, concerning prostaglandins and leukotrienes, are important to remember?

• INFLAMMATION
• These lipids are synthesized from the dietary fat linoleic acid
○ Converted to arachadonic acid and then to prostaglandin by COX
• Arachadonic acid can also be converted to leukotrienes via 5-lipoxygenase
• Prostaglandins are important in fever generation and inflammation
• COX inhibitors are used clinically as anti-inflammatory agents
• Leukotrienes are also important in inflammation and inhibitors of 5-lipoxygenase are used in asthma treatment