| First Author | Goudarzi M | Year | 2013 |
| Journal | Toxicology | Volume | 311 |
| Issue | 3 | Pages | 87-98 |
| PubMed ID | 23851158 | Mgi Jnum | J:315295 |
| Mgi Id | MGI:6830029 | Doi | 10.1016/j.tox.2013.07.002 |
| Citation | Goudarzi M, et al. (2013) PPARbeta/delta modulates ethanol-induced hepatic effects by decreasing pyridoxal kinase activity. Toxicology 311(3):87-98 |
| abstractText | Because of the significant morbidity and lethality caused by alcoholic liver disease (ALD), there remains a need to elucidate the regulatory mechanisms that can be targeted to prevent and treat ALD. Toward this goal, minimally invasive biomarker discovery represents an outstanding approach for these purposes. The mechanisms underlying ALD include hepatic lipid accumulation. As the peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) has been shown to inhibit steatosis, the present study examined the role of PPARbeta/delta in ALD coupling metabolomic, biochemical and molecular biological analyses. Wild-type and Pparbeta/delta-null mice were fed either a control or 4% ethanol diet and examined after 4-7 months of treatment. Ethanol fed Pparbeta/delta-null mice exhibited steatosis after short-term treatment compared to controls, the latter effect appeared to be due to increased activity of sterol regulatory element binding protein 1c (SREBP1c). The wild-type and Pparbeta/delta-null mice fed the control diet showed clear differences in their urinary metabolomic profiles. In particular, metabolites associated with arginine and proline metabolism, and glycerolipid metabolism, were markedly different between genotypes suggesting a constitutive role for PPARbeta/delta in the metabolism of these amino acids. Interestingly, urinary excretion of taurine was present in ethanol-fed wild-type mice but markedly lower in similarly treated Pparbeta/delta-null mice. Evidence suggests that PPARbeta/delta modulates pyridoxal kinase activity by altering Km, consistent with the observed decreased in urinary taurine excretion. These data collectively suggest that PPARbeta/delta prevents ethanol-induced hepatic effects by inhibiting hepatic lipogenesis, modulation of amino acid metabolism, and altering pyridoxal kinase activity. |
