title: PPARβ/δ modulates ethanol-induced hepatic effects by decreasing pyridoxal kinase activity.
abstract: 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-β/δ (PPARβ/δ) has been shown to inhibit steatosis, the present study examined the role of PPARβ/δ in ALD coupling metabolomic, biochemical and molecular biological analyses. Wild-type and Pparβ/δ-null mice were fed either a control or 4% ethanol diet and examined after 4-7 months of treatment. Ethanol fed Pparβ/δ-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 Pparβ/δ-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 PPARβ/δ 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 Pparβ/δ-null mice. Evidence suggests that PPARβ/δ modulates pyridoxal kinase activity by altering Km, consistent with the observed decreased in urinary taurine excretion. These data collectively suggest that PPARβ/δ prevents ethanol-induced hepatic effects by inhibiting hepatic lipogenesis, modulation of amino acid metabolism, and altering pyridoxal kinase activity.
authors.affiliation: Lombardi Comprehensive Cancer Center, Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC, USA.
authors.forename: Maryam
authors.initials: M
authors.lastname: Goudarzi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Koga
authors.forename: Combiz
authors.initials: C
authors.lastname: Khozoie
authors.forename: Tytus D
authors.initials: TD
authors.lastname: Mak
authors.forename: Boo-Hyon
authors.initials: BH
authors.lastname: Kang
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Fornace
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Peters
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood; D001806:Blood Urea Nitrogen; D000431:Ethanol; D008108:Liver Diseases, Alcoholic / Q000378:metabolism* / Q000473:pathology; D008297:Male; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D048068:PPAR-beta / Q000235:genetics / Q000378:metabolism*; D011731:Pyridoxal Kinase / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014556:Urine / Q000737:chemistry
chemical_list: D000596:Amino Acids; D001647:Bile Acids and Salts; D047494:PPAR delta; D048068:PPAR-beta; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D000431:Ethanol; D000410:Alanine Transaminase; D011731:Pyridoxal Kinase; D000469:Alkaline Phosphatase
keywords: Alcoholic liver disease; Metabolomics; Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ); Pyridoxal kinase