Fatty Acids as Naturally Occuring Ligands for Cell Receptors

1
Fatty Acids as Naturally Occuring Ligands for
Cell Receptors
Martha A. Belury, PhD, RD 2-1680 Belury.1_at_osu.edu
2
Fatty Acids as Xenobiotics

• CLA as Prototype of a Bioactive Fatty Acid
• Physiological Roles of CLA
• Transactivation of PPARs by CLA
• Clinical Significance of CLA
• Metabolism and Other Natural Things
• Compare and Contrast

3
Health Properties of Conjugated Linoleic Acid

• Anti-Tumorigenic
• Anti-Diabetogenic
• Anti-Lipogenic (and pro-lipolytic)
• Pro-Anabolic for Muscle
• Anti-Atherosclerotic

4
CLA Reduces Body Weight
Belury et al., Nutr Cancer 26 149-156, 1996
5
CLA Lowers Adiposity

• Mice
• Rats
• Chickens
• Pigs
• Cattle
• Humans

• Park et al., 1997
• Houseknecht et al., 1998
• Cook et al., 1994
• Eggert et al., 2001
• Bauman et al., 1999
• Vessby et al., 2000

6
CLA Delays Onset of Impaired Glucose Tolerance

• ZDF Rat Model
• Pre-Diabetic Rats 8 wks old
• Fed CONTROL, 1.5 CLA, or TZD Diet
• 2 Weeks, 8-10 weeks of age

Biochem Biophys Res Comm 244 678-682 (1998)
7
PPAR Ligands
Cl
O
Monoethylhexylphthate
N
N
O
Wy 14,643
O
N
O
O
C
H
C
H
S
3
3
O
C
H
3
O
Clofibric Acid
Cl
O
C
H
O
3
O
C
H
3
Clobuzarit
Cl
O
O
C
H
3
C
H
3
O
O
C
H
Nafenopin
3
O
O
Fenofibrate
Cl
O
O
C
H
3
O
C
H
3
O
C
H
3
O
N
N
Cl
O
O
C
H
3
LY 171883
C
H
(
C
H
)
n
O
2
2
C
H
Methylclofenapate
N
3
N
C
H
O
H
3
7
C
H
3
O
O
Bezafibrate
N
Cl
O
Cl
C
O
N
H
S
O
C
H
2
3
O
C
H
3
O
O
Fomesafen

O
C
F
N
3
C
H
3
O
O
Ciprofibrate
O
Cl
C
H
O
3
F
Cl
O
F
F
O
F
F
F
F
F
F
F
O
O
F
F
F
F
Conjugated linoleic acid
F
F
F
F
F
Perfluorodecanoic acid
O
O
N
O
O
S
O
Troglitazone
Arachidonic acid
O
Prostaglandin J2
O
O
O
8
Dietary Fatty Acids
FA- PPARn
RXR- 9CisRA
FA PPARn
Cytosol
PPRE Target Gene
Nucleus
9
b-Cell Dysfunction
Insulin Resistance
Type 2 Diabetes Mellitus (T2 DM)
10
Linoleic acid, C182 n6
CLA, C182
?6 Desaturase
?-Linolenic Acid,C183 n6
C183
Activate PPARg
Elongase
DGLA,C203 n6
C203
?5 Desaturase
Arachidonate (AA) C204 n6
Conjugated-AA,C204
11
Eicosanoids
Linoleic Acid Or CLA
Membrane Phospholipids
Phospholipase A2
AA (204) Or C- AA (204)
Linoleic Acid Or CLA
Cyclooxygenases
Lipoxygenases
HPETE
Prostaglandins Thromboxanes
PGD2, PGE2,PGF2
Leukotrienes
Inflammatory and Tumor promotion related events
Inflammatory related events
12
Systemic View How CLA May Impact Macronutrient
Metabolism
Pancreas

• (?) PEPCK
• LPL

Adipose

• ACO, FABP, CYP4A
• ?ApoC-III ? LPL ? b-oxidation
• PEPCK ? ? Gluconeogenesis
• MKP-1 ? ? MAP-K
• Insulin action

Glucose
Liver
Muscle