We aimed to investigate the effect of atorvastatin (5 and 30 mg/kg/day for 2 weeks) on hepatic lipid metabolism in a well established model of dietary hypertriglyceridemia, the fructosefed rat. Fructose feeding (10% fructose in drinking water for 2 weeks) induced hepatic lipogenesis and reduced peroxisome proliferator-activated receptor ␣ (PPAR␣) expression and fatty acid oxidation. As a result, plasma and liver triglyceride and plasma apolipoprotein B (apoB) levels were increased. Atorvastatin, 5 and 30 mg/kg during 2 weeks, markedly reduced plasma triglyceride, but decreased apoB levels only at the highest dose tested (50%). Triglyceride biosynthetic enzymes and microsomal triglyceride transfer protein were unchanged, whereas liver PPAR␣, acyl-CoA oxidase, and carnitine palmitoyltransferase I mRNA levels (1.9-, 1.25-, and 3.4-fold, respectively) and hepatic fatty acid ␤-oxidation activity (1.25-fold) were increased by atorvastatin at 30 mg/kg. Furthermore, hepatic triglyceride content (45%) and plasma nonesterified fatty acids (NEFAs) (49%) were reduced. These results show for the first time that liver triglyceride increase in fructose-fed rats is linked to decreased expression of PPAR␣, which is prevented by atorvastatin treatment. The increase in PPAR␣ expression caused by atorvastatin was associated with reduced liver triglyceride and plasma NEFA levels.

The butanolic fraction (BT-ll) derived from the aqueous crude extract was prepared from aerial parts of Baccharis trimera and assessed in anti-inflammatory, analgesia, and ulcerogenesis models. Intraperitoneal pretreatment with lyophilized BT-ll, at doses ranging from 40 to 100mg/kg, markedly inhibited carrageenan-and dextran-induced inflammation (70.4-90.8% and 25.7-71.3%, respectively) and weakly decreased C16-paf-and arachidonic acid-induced swelling (24.9-36.7% and 0-30.6%, respectively). No effect was observed, at the same doses, on zymosan-induced edema. The intraperitoneal examination indicates that the anti-phlogistic action of BT-ll was not due to an irritating effect at the injection site. Besides, BT-Il reduced abdominal constrictions in mice following injection of acetic acid: at 50mg/kg, it gave 67.4% inhibition and, at 100mg/kg, 95.1 %. The ulcerogenic assay showed that the incidence of ulcers after BT-ll i.p. treatment was 2/6 at 50mg/kg and 6/6 at 100mg/kg. Ulcerogenic indices were 1.3 0.5 and 2.7 0.8, respectively.These results indicate that B. trimera shows strong antiinflammatory and analgesic properties which seem to be due, at least partly, to the inhibition of prostaglandin biosynthesis. The chromatographic separation of BT-II monitored by bio-assay (carrageenan-induced edema test in mice) was carried out. The active constituents were found to be mainly saponins in which echinocystic acid (or its enantiomer) is the major aglycone, and also rutin.Key words: Baccharis trimera, Asteraceae, anti-inflammatory activity, analgesic effect, rutin, saponins, echinocystic acid. and a steroid (9) have been identified in B. trimera extracts. The flavonoids showed antihepatotoxic (8) and molluscicidal (6) properties. Recently, we have reported on the anti-phlogistic effect produced intraperitoneally by B. trimera-aqueous extract and its butanolic fraction (BT-Il). BT-lI markedly inhibited carrageenan-induced edema in a dose-dependent manner Planta Medica 62(1996)232-235 © Georg Thieme Verlag Stuttgart. New York (DE5O = 26.7mg/kg), reaching values near 100% inhibition of inflammation (10).In the present study, the anti-inflammatory, analgesic, and ulcerogenic effects of BT-ll are evaluated. The findings indicate that this fraction possesses active principles capable of preventing various chemically-induced edemas in rats and abdominal writhings following acetic acid injection in mice.Irritating and ulcerogenic effects are also evaluated. The chromatographic fractionation of BT-II, monitored by bio-assay revealed that the active constituents are rutin and, mainly, a saponin mixture in which echinocystic acid or its enantiomer is the major aglycone. Materials and MethodsPlant material B. trimera was collected in Uruguay during the flowering season. A voucher specimen has been deposited at the BCF herbarium (Fac. of Pharmacy, Univ. of Barcelona) under the number 36688. Chromatographic and spectroscopic methods CC stationary phases were polyamide CC-6 (Macherey and Nagel, Düren, Germany) and Sephadex LH-20 (P...

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The molecular mechanisms by which peroxisome proliferator-activated receptor (PPAR) activation by fibrates reduces fat deposition and improves insulin sensitivity are not completely understood. We report that exposure of a rat primary culture of adipocytes for 24 h to the PPAR activator bezafibrate increased the mRNA levels of crucial genes involved in peroxisomal and mitochondrial ␤-oxidation. The mRNA levels of the peroxisomal ␤-oxidation rate-limiting enzyme acyl-CoA oxidase and of the muscle-type carnitine palmitoyl transferase I (M-CPT-I), which determines the flux of mitochondrial ␤-oxidation, increased by 1.6-fold (P < 0.02) and 4.5-fold (P ‫؍‬ 0.001), respectively. These changes were accompanied by an increase in the transcript levels of the uncoupling protein-2 (UCP-2; 1.5-fold induction; P < 0.05) and UCP-3 (3.7-fold induction; P < 0.001), mitochondrial proteins that reduce ATP yield and may facilitate the oxidation of fatty acids. Furthermore, bezafibrate increased the mRNA levels of the fatty acid translocase (2-fold induction; P < 0.01), suggesting a higher fatty acid uptake into adipocytes. In agreement with these changes, bezafibrate caused a 1.9-fold induction (P < 0.02) in 9,10-[ 3 H]palmitate oxidation. Moreover, bezafibrate reduced the mRNA expression of several adipocyte markers, including PPAR␥ (30% reduction; P ‫؍‬ 0.05), tumor necrosis factor-␣ (33% reduction; P < 0.05), and the ob gene (26% reduction). In contrast, adipocyte fatty acid binding protein mRNA levels increased (1.5-fold induction; P < 0.01), pointing to a mobilization of fatty acids to mitochondria and peroxisomes. The reduction of the adipocyte markers caused by bezafibrate was accompanied by an increase in the mRNA levels of the preadipocyte marker Pref-1 (1.6-fold induction; P < 0.01). Some of the changes observed in the primary culture of rat adipocytes also were studied in the epididymal white adipose tissue of bezafibrate-treated rats for 7 days. In vivo, M-CPT-I mRNA levels increased (4.5-fold induction; P ‫؍‬ 0.001) in epididymal white adipose tissue of bezafibrate-treated rats. Similarly, fatty acid translocase (2.6-fold induction; P ‫؍‬ 0.002) and Pref-1 (5.6-fold induction) mRNA levels increased, although differences in the latter were not significant because of huge individual variations. These results indicate that exposure of adipocytes to bezafibrate, independent of its hepatic effects, increases the degradation of fatty acids, reducing their availability to synthesize triglycerides. As a result, some degree of dedifferentiation of adipocytes to preadipocyte-like cells is achieved. These changes may be involved in the reduction in fat depots and in the improvement of insulin sensitivity observed after bezafibrate treatment.