E3 FFA

Question 1

describe FA structure

- types of FA

Answer 1

Fatty acids –> carboxylic acid linked to an aliphatic tail (varying chain length)

• Short chain fatty acids (SCFA) – <6 carbon chain —> Saturated fatty acids (SFA)
• Medium chain fatty acids (MCFA) – 7-12 carbon chain —> Monounsaturated (MUFA)
• Long chain fatty acids (LCFA) - >13 carbon chain —> Polyunsaturated (PUFA)

Question 2

describe MCFAs and LCFAs

Answer 2

• Obtained from dietary fat
• de novo synthesis in the liver
• Essential FAs (Linoleic acid) helps synthesis of PUFA
• Precursors of signalling molecules (PG’s and LT’s)

Question 3

describe SCFAs

Answer 3

• Produced when dietary fiber is fermented in colon

- Microbiota of the gut (Rise in interest in ‘Gut Flora’)

Question 4

Name the GPCR for fatty acids

Answer 4

Four family members:FFA1-FFA4

• SCFA = FFA2 and FFA3 receptors
• LCFA / MCFA = FFA1 and FFA4 receptors
• Synthetic ligands = FFA1, FFA2, FFA4 (Orthosteric)
• Synthetic ligands = FFA1-FFA3 (Allosteric)

Question 5

what receptor was deorphanized in 2003

Answer 5

FFA1
Originally designated GPR40
Crystal structure resolved (2015)

Question 6

FA1 involved in which body sytems

Answer 6

CNS, taste buds, pancreatic B cells, Enteroendocrine I, K, L cells, Osteociast & osteoblasr, BM-derviveed cells

Question 7

Name enteroendocrine cell subpops in GI

Answer 7

Ghrelin: A (x-like) cells 
Gastrin: G cell  
Somatostatin: D cell  
CCK/ 5HT: I cell
GIP/5HT: K cell 
GLP-1, GLP2, PYY, 5HT: L cell 
5HT: EC cells

Question 8

Acute LCFA treatment results in
what happens as a consqeuence of chronic LCFA

MCFA as drugs are

Answer 8

• enhanced glucose-dependent insulin secretion (GSIS)
• lipotoxicity and inhibition of insulin secretion
• poor agonists

Question 9

Name FFAR1 Endogenous agonists

the FFA1 receptor is a drug target for what?
what is FFA1 receptors other name

Answer 9

a-linolenic acid(ALA)
& docosahexaenoic acid(DHA)

Promising antidiabetic target (agonist)
FFA1r = GPR40

Question 10

describe the drug Fasiglifam (TAK875)

Answer 10

aim: Treatment of Type 2 diabetes
discontinued due to liver toxicity –> off target inhibition of hepatobiliary transporters (at least three allosterically linked binding sites)

Question 11

compare bias agonists FFA1 R & LCFA to full agonist AM1638

Answer 11

TAK875 –> FFA1 –> Arr2/3
Arrestin KO mice –> insulintropic activity reduced

LCFAs –> FFA1 –> Gq
Gq inhibition –> insulintrophic activity ablated

AM1638 –> full agonist
= More effective in regulating blood glucose
insulin levels
Effects with GLP-1, GIP, and insulin levels were seen only with the full agonist AM 1638

Question 12

name some Existing anti-diabetic drugs - FFA1 agonists:

Answer 12

Rosiglitazone
Netoglitazone
Troglitazone