Dk. Asiedu et al., ACUTE MODULATION OF RAT HEPATIC LIPID-METABOLISM BY SULFUR-SUBSTITUTED FATTY-ACID ANALOGS, Biochemical pharmacology, 49(7), 1995, pp. 1013-1022
A single oral dose of two 3-thia (3-thiadicarboxylic and tetradecylthi
oacetic acids) and of 4-thia (tetradecylthiopropionic acid) fatty acid
s were administered to normolipidemic rats and their effects on lipid
metabolism over a 24 hr period were, studied. All three thia fatty aci
ds could be detected in plasma 2 hr after treatment. Tetradecylthioace
tic and tetradecylthiopropionic acids were detected in different hepat
ic lipid fractions but were incorporated mainly into hepatic phospholi
pids. Two hours after administration hepatic mitochondrial beta-oxidat
ion and the total liver level of long-chain fatty acyl-CoA increased w
ith a concomitant decrease in saturated fatty acids, total hepatic mal
onyl-CoA and plasma triacylglycerol levels in the 3-thia fatty acid gr
oups. Tetradecylthiopropionic acid administration caused a decrease in
mitochondrial beta-oxidation and an increase in plasma triacylglycero
l at 24 hr. The activities of key lipogenic enzymes were unaffected in
all treatment groups. Plasma cholesterol level was reduced only at 8
hr in 3-thiadicarboxylic acid treated rats although 3-hydroxy-3-methyl
glutaryl-CoA (HMG-CoA) reductase was suppressed already at 2, 4, 8 and
12 hr. The results show that thia fatty acids are rapidly absorbed an
d are systemically available after oral administration but the 3-thia
fatty acids reached systemic circulation more slowly and less complete
ly than the 4-thia fatty acid. Very low levels of the thia fatty acids
are detected in plasma 24 hr after a single administration. They are
incorporated into all hepatic lipid classes, especially phospholipids.
Rapid incorporation of a non beta-oxidizable thia fatty acid into hep
atic lipids may cause a diversion of other fatty acids from glycerolip
id biosynthesis to mitochondrial beta-oxidation. Stimulation of mitoch
ondrial beta-oxidation and suppression of HMG-CoA reductase are primar
y events, occurring within hours, after 3-thia fatty acid administrati
on. The hypotriglyceridemic effect of the 3-thia fatty acids observed
at 2-3 hr is independent of the activities of key lipogenic and triacy
lglycerol synthesising enzymes.