Changes in hepatic lipid metabolism associated with lipid accumulation and its reversal in rats given the peroxisome proliferator LY171883

Cysteinyl Leukotriene Receptor 1/2 Antagonists Nonselectively Modulate Organic Anion Transport by Multidrug Resistance Proteins (MRP1-4)

“…In contrast, these same three CysLT 1 R-selective LTMs exerted only inhibitory effects on MRP3. However, this was not the case for LY171883, a CysLT 1 R antagonist that can also act as a phosphodiesterase inhibitor (Fleisch et al, 1985) and a peroxisome-proliferating agent (Foxworthy et al, 1990). Thus, LY171883 only stimulated E 2 17bG uptake by MRP2 and MRP3 (up to 4-fold and 2-fold, respectively) and did not exert the biphasic actions of the other CysLT 1 R-selective LTMs, at least at the concentrations tested, which include those likely to be used in vesicular transport studies in vitro.…”

Triglyceride Accumulation by Peroxisome Proliferators in Rat Hepatocytes

“…The relationship between TG fluctuation and peroxisomal induction, including the peroxisome proliferation, the induction of several proteins, and increase in enzyme activities by PxPs, has not been fully elucidated, though an increase in Pxox activity and a reduction in hepatic TG level, 9,22) or contrarily, the activity and hepatic TG accumulation 11,18,19) in vivo have been reported. Two mechanisms of Px induction 32) have been proposed: 1) the receptor mediated theory, termed PPARs by Isseman et al, 4) which does not rule out the possibility that PxPs interact indirectly with the receptor, and 2) substrate overload, termed lipid pertubation, which is caused by a high cellular level of long acyl CoA 20) and PxP metabolites, the corresponding CoA thioesters.…”

“…35,36) There are several studies that hepatic peroxisomal inductions and the TG lowering effect by fibrates are not directly related. [8][9][10] According to a report by Foxworthy et al, 19) the sequence of events in the liver after administration of PxPs to rats, including transient hepatic TG accumulation in the early stage, followed by an increase in Px-ox, implies that hepatic TG accumulation is responsible for the induction of Px-ox. However, hepatic lipid accumulation by chlorpromazine administration resulted in no indication of Px-ox activity in rats, 37) in accordance with the results of Brefeldin A treatment (Fig.…”

“…A linear increasing correlation between Px-ox activity and cellular long chain fatty acid level by PxP was reported in rat cultured hepatocytes, 16) leading to hepatic TG accumulation when the TG synthesis process was completed, as well as a fibrate and a long chain fatty acid enhanced cellular TG level with a increase in Px-ox activity. 17) In in vivo experiments, PxPs including fatty acid analogues enhanced hepatic TG accumulation, 11,18,19) or in contrast, decrease it, [20][21][22] when the increase in Px-ox activity and the decrease in plasma TG were simultaneously observed. These discrepancy results could be due to the fact that physiological lipid metabolism is regulated by complicated, precise, and divers endogenous factors.…”

Species specificity in the blood cholesterol‐lowering effect of YM‐16638

“…(Feuer, 1977;Dhai, 1979) that the serum ALT lowering effect is due to the thiadiazol structure at 3-methyl position of the YM-16638 molecule; however, we still have insufficient data to confirm this point. LY-171883 (Eli Lilly Co., Ltd., U.S.A.), a potent and leukotriene antagonist with a similar structure to YM-16638, (Marshall et al, 1987;Fleisch et al, 1985) is known to decrease serum triglyceride level in rats and monkeys, but not serum cholesterol level and ALT activity (Eacho et al, 1985;Foxworthy et al, 1990;Hoover et al, 1990).…”