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

Abstract

-The effects of the peroxisome proliferator, dehydroepiandrosterone sulfate (DHEAS), and the typical cytochrome P450 (CYP) inducers phenobarbital (PB) and 3-methylcholanthrene (3-MC) on fatty liver were examined in rats. Treating rats with orotic acid caused marked accumulation of lipid droplets in the liver. This effect of orotic acid was almost eradicated by co-treatment with DHEAS and PB. While DHEAS or PB alone also alleviated fatty liver, treatment with 3-MC caused little effect on a reduction in lipid droplets. Histopathological examinations revealed numerous peroxisomes in the liver of rats treated with DHEAS. In addition, a significant increase in the expression on hepatic CYPs was observed in rats the fatty liver of which was attenuated. Regarding other enzymes associated with hepatic fatty acid oxidation, the expression levels of sirtuin 1, sirtuin 6, and carnitine palmitoyltransferase 1 were also upregulated most markedly by treatment with DHEAS alone. Thus, the attenuation in fatty liver observed in the present study is likely due to peroxisome proliferation and the induction of fatty acid-metabolizing enzymes by DHEAS and typical CYP inducers.

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

“…Considering that fructose is easily metabolized to glycerin and fatty acid, it is quickly converted to TG. In our previous studies, a combination of orotic acid/sucrose was used for 4 weeks to recapitulate the marked accumulation of lipid droplets in hepatocytes ( Goto et al ., 1998a( Goto et al ., , 1998bTakeuchi et al ., 2015Takeuchi et al ., , 2018. These observations were also supported by the present study, in which the supplementation period of orotic acid/ sucrose was extended to 8 weeks to reduce variations in fatty liver formation.…”

“…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).…”

“…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). Furthermore, we have reported that the combination treatment of the niacin metabolite N 1 -methylnicotinamide (MNA) and the aldehyde oxidase (AO) inhibitor hydralazine (HYD) improved fatty liver in the same NAFL model rats (Takeuchi et al, 2018).…”

DNA Methyltransferases Modulate Hepatogenic Lineage Plasticity of Mesenchymal Stromal Cells

“…Hep-converted MLCs have proliferation ability and higher hepatic lineage potential (Figure 7B). Therefore, these cells may also serve as an alternative cell source for liver regeneration (Du et al., 2014, Takeuchi et al., 2015). …”