Lipid diseases

Question 1

Lipodystrophy

Answer 1

• Mutant perlipin -> no protection of TG from lipolysis by HSL
• Opposite: obesity, where perlipin expression is increased

Question 2

Neimann-Pick A/B

Answer 2

• Sphingomyelinase deficiency
• Accumulation of sphingomyelin, causing fat accumulation in
• CNS (type A, severe)
• Other tissues Þ hepatosplenomegaly (type B, less severe)
• fatal

Question 3

Smith-Lemli-Opitz

Answer 3

• Relatively common AR disease
• Partial deficiency in 7-dehyrdocholesterol-7-reductase
• Affects embryonic development Þ Multisystem abnormalities

Question 4

Neimann-Pick C

Answer 4

• Delayed release of free cholesterol from lysosomes following LDL intake into cells
• NPC-1 and NPC-2 genes encode membrane proteins that bind with high affinity to cholesterol within the endosome/lysosome
• Accumulation of LDL contents (unesterified cholesterol, sphingomyelin, phospholipids, glycolipids – especially GM2 gangliosides) in lysosomes of
• CNS Þ Progressive neural damage
• Other tissues Þ hepatosplenomegaly
• Slow progress through childhood and eventual death
• Accumulation of sphingomyelin is only secondary (in contrast to being primary in NP A/B)

Question 5

Sphingolipidosis

Answer 5

• Defective/absent sphingolipid degradation enzyme

* Accumulation of sphingolipids in lysosomes

Question 6

Tay-Sachs disease

Answer 6

• Defective β-N-acetyl-hexosaminidase (Hex A), required for GM2 ganglioside breakdown in lysosomes by sequential removal of their sugars (hexose by Hex A, etc)
• Accumulation of GM2 ganglioside in neurons Þ neuronal swelling and damage
• 1 y/o Þ Neural problems ÞÞÞ death
• Amniotic fluid assay can be done to test the enzyme’s activity

Question 7

Tangier’s disease

Answer 7

• Defective ABCA1 (ABC transporter A1)
• ABCA1 is needed to lipidaate apoA 1 = transport cholesterol esters and phospholipids from cell to PM where apoA1 is.
• This results in formation of nascent, discoidal HDL
• No lipidation Þ apoA1 degradation and failure to make HDL
• Absent apoA1 and HDL

Question 8

Cholesterol drugs

Answer 8

• Statins – competitively inhibit HMG coA reductase Þ block cholesterol synthesis
• Cholystyramin: this insoluble resin’s positive charge sequesters bile salts in gut and prevents their reabsorption Þ decrease recycling of bile acids and thus drain their cholesterol source
• Orlistat (p. 132, p. 297)
• Pancreatic and gastric lipase inhibitor Þ ¯ TG digestion Þ ¯ FA absorption
• SE:
• Malabsorption of fat-soluble vitamins Þ use supplements
• Loose, fatty stool

Question 9

Cholelithiasis

Answer 9

1. Decrease of Bile acids in bile, due to
   * Intestinal malabsorption of bile acids
   * Liver failure to produce bile acids
   * Obstruction of biliary tract
2. Increased biliary cholesterol excretion
   * Example: use of fibrates
   * Results in secretion of more cholesterol than can be solublilized (cholesterol is hydrophobic; conjugation to bile acids and salts is what solublizes it) Þ crystallization Þ gallstone formation
   * Rx
   * Surgical removal of gallbladder
   * Chenodeoxycholic acid to solublize more cholesterol

Question 10

Lipid malabsorption

Answer 10

• Causes
• CF
• Pancreatic insufficiency that affects pancreatic lipase and digestion of lipids
• Pancreatic lipase deficiency makes milk fat digestion in neonates a function of salivary and gastric lipases
• Shortened bowel (¯ absorption)
• Results
• FA in feces Þ steatorrhea
• loss of fat-soluble vitamins (ADEK)

Question 11

Type I hyperlipoproteinemia

Answer 11

• Lack of lipoprotein lipase function (direct, or because we lack the apoCII, the apoprotein on the mature chylomicron which activates the enzyme)
• No chylmicron breakdownÞDramatic accumulation of chylomicrons Þ hyperTAGemia

Question 12

Type III hyperlipoproteinemia

Answer 12

• Individuals who are homozygotic for the e2 isoform of apoE
• apoE is the apoprotein of chylomicron remnants that’s necessary for their uptake by the liver’s chylomicron remnant receptors.
• apoE has several isoforms.
• E3 is the most common (>50%)
• e2 binds poorly to the receptor
• e4 isn’t great either, as it’s associated with late-onset Alzheimer’s disease
• apoE2 binds poorly to hepatic chylomicron remnant receptor Þ defective uptake of chylomicron remnants and IDLs Þ hypercholesterolemia and atherosclerosis

Question 13

Type II Hyperlipoproteinemia

Answer 13

• Defective LDL uptake receptors
• -vely charged glycoproteins assembled in clathrin-coated pits
• Results in
• elevation of plasma LDL and cholesterol Þ hyperlipid/cholesterolemia and premature atherosclerosis
• foam cell formation as follows:
• Mϕs cannot uptake native LDL, but will internalize LDL after chemical modification, and this internalized modified (oxidized), non-native LDL converts the Mϕs to foamy cells
• This uptake is mediated by scavenger receptors, especially SRA1, which recognizes the increasing –ve charge on the modified LDL protein.
• SRAs exist ONLY on Mϕs, not on endothelial cells
• The internalized oxidized LDL will then be used by ACAT to produce cholesteryl esters, turning cells foamy
• Oxidized LDL is chemotactic for monocytes, but ¯ motility of resident Mϕs Þ they accumulate in intima
• Oxidized LDL is also cytotoxic to cells Þ may cause some of the necrotic injury to endothelium Þ platelets can now adhere to subendothelium and further atherosclerotic injury

Question 14

Abetalipoproteinemia

Answer 14

• Rare case caused by defective MTTP (microsomal TAG transfer protein) Þ inability to load apoB (48 for chylomicron, 100 for VLDL and LDL) with cholesterol, PLs, and TAG
• Results:
• No chylomicrons or VLDLs are formed
• TAGs accumulate in intestine and liver

Question 15

Fatty liver

Answer 15

• Imbalance between hepatic TAG synthesis and secretion of VLDL
• Caused by problems including
• Obesity
• Uncontrolled DM
• Chronic ethanol ingestion
• Maybe because alcohol caused hypoglycemia by using up the NAD+ that would otherwise be used for the malate shuttle that’s required for gluconeogensis Þ divert glucose to fatty acid synthesis