Prevention of Orotic-Acid-Induced Fatty Liver in Male Rats by Dehydroepiandrosterone and/or Phenobarbital.

Abstract

ABSTRACT. Dehydroepiandrosterone (DHEA) is a steroid hormone which induces the peroxisome proliferation in rodents. The fatty liver induced by orotic acid and a high sucrose diet in male rats was prevented by the administration of DHEA and/or phenobarbital (PB). A significant increase in the liver weight was induced in the DHEA group (relative weight) and the DHEA + PB group (absolute and relative weight). The liver weight increased more conspicuously in the DHEA + PB group than in the DHEA group. The increase in the liver weight was caused by an increase in the cell size and peroxisome number. In addition, the administration of DHEA alone and the combination of DHEA and PB prevented the lipid droplet accumulation in hepatocytes. The administration of PB alone also prevented the accumulation of lipid droplets without any increase in the liver weight. -KEY WORDS: dehydroepiandrosterone, fatty liver, orotic acid, peroxisome proliferator, phenobarbital.J. Vet. Med. Sci. 60(4): 513-517, 1998 to 60%, a ventilation frequency of 13 to 15 air exchanges/ hr, and a 12-hr light/12-hr dark cycle (lights on: 07:00 to 19:00 hr). Control animals were fed the standard food for 2 weeks, and DHEA group rats were fed the standard food with 0.5% DHEA (Sigma Chemical Co.). Animals in the PB group were fed the standard food and intraperitoneally injected with 6% PB (Wako Pure Chemicals Co.) at 60 mg/ kg, once a day, 5 days a week, for 2 weeks. The DHEA + PB group were fed standard food with concomitant treatment with DHEA and PB. Body weight and food consumption were measured every 7 days. The final body weight was measured on the day of necropsy to calculate the relative organ weight. All animals were euthanized by exsanguination from abdominal veins and arteries following ether anesthesia and laparotomy. They were then examined for gross findings, and the absolute of the liver and organto-body weight ratio (relative weight) were determined. The liver of all animals was fixed in 10% neutral formalin, embedded in paraffin, sectioned at 3 µm, and stained with hematoxylin and eosin. For peroxisome visualization in the control and DHEA + PB groups, 45-µm-thick tissue slices fixed in 2.5% glutaraldehyde were reacted for 60 min at 37°C in alkaline 3,3'-diaminobenzidine medium [20] and postfixed in 1% OsO 4 . They were then embedded in epoxy resin, and 1 µm semi-thin sections were stained with toluidine blue. Statistical analysis: Body weight gain, food consumption, and organ weight were analyzed by one-way analysis of variance. When one-way analysis yielded a significant difference (P<0.05), the values were analyzed by Dunnett's test. RESULTSIn comparison with the control group, significant Dehydroepiandrosterone (3β-hydroxy-5-androsten-17-one, DHEA) is a metabolic intermediate in the testosterone, estrone, and estradiol synthesis pathway mainly in the human adrenal cortex and rodent gonads [1,28]. The actions of this hormone reported thus far included a possible antiobesity effect [2,16], preventive action on the development of athero...

Dehydroepiandrosterone sulfate and cytochrome P450 inducers alleviate fatty liver in male rats fed an orotic acid-supplemented diet

“…In addition, the TG accumulation induced by orotic acid is facilitated by a high-sucrose diet (Novikoff et al, 1974). Our early studies reproduced the marked accumulation of lipid droplets in hepatocytes using a combination of treatments with orotic acid and sucrose (Goto et al, 1998a(Goto et al, , 1998b). These observations were also supported by those from the present study.…”

“…A previous study has already revealed that unconjugated DHEA, PB or a combination of the two prevents orotic acid-induced fatty liver in male rats (Goto et al, 1998a). The preventive effect of DHEA acetate has also been reported (Goto et al, 1998b).…”

“…A previous study aiming to identify ways to alleviate fatty liver has demonstrated that dehydroepiandrosterone (DHEA) and its co-administration with phenobarbital (PB), which are a peroxisome proliferator and a typical CYP2B inducer, respectively, prevent the accumulation of lipid droplet in the fatty liver induced by feeding male rats with diets containing orotic acid and sucrose at a high level (Goto et al, 1998a). In this context, it was suggested that the reduced form of dehydroepiandrosterone sulfate (DHEAS) in the serum is a useful biomarker for the diagnosis of non-alcoholic fatty liver disease (NAFLD) (Tokushige et al, 2013).…”

Reduction of fatty liver in rats by nicotinamide via the regeneration of the methionine cycle and the inhibition of aldehyde oxidase

“…From this perspective, we examined the effect of some compounds on fatty liver improvement by using NAFL model rats induced by orotic acid with a highsucrose diet, in which the disease level of fatty liver is relatively mild. Our previous research showed that some compounds alleviated fatty liver following the administration of the peroxisome proliferator dehydroepiandrosterone sulfate (DHEAS) and/or the administration of the cytochrome P450 (CYP) inducer phenobarbital (PB) to NAFL model rats induced by orotic acid with a highsucrose diet (Goto et al, 1998a(Goto et al, , 1998bTakeuchi et al, 2015). The lipid droplets were significantly reduced from the fatty liver as a consequence of enhancing the metabolic reaction (Goto et al, 1998a(Goto et al, , 1998bTakeuchi et al, 2015).…”

Effects of Fatty Liver Induced by Niacin-free Diet with Orotic Acid on the Metabolism of Tryptophan to Niacin in Rats

“…8) Furthermore, it has been reported that increased triglyceride synthesis mediated by changes in liver phosphatidate phosphohydrolase activity was involved in the hepatic triglyceride accumulation induced by orotic acid administration and that this change was markedly suppressed by dietary n-3 fatty acids. 9) Goto et al 10) also have been reported that dehydroepiandrosterone, as well as cloˆbrate, may prevent orotic-acid-induced fatty liver.…”