PPARβ/δ modulates ethanol-induced hepatic effects by decreasing pyridoxal kinase activity

Maryam Goudarzi, Takayuki Koga, Combiz Khozoie, Tytus D. Mac, Boo Hyon Kang, Albert J. Fornace, Jeffrey M. Peters

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)87-98
Number of pages12
JournalToxicology
Volume311
Issue number3
DOIs
StatePublished - Sep 5 2013

Fingerprint

Pyridoxal Kinase
Peroxisome Proliferator-Activated Receptors
Alcoholic Liver Diseases
Ethanol
Metabolism
Liver
Metabolomics
Taurine
Nutrition
Sterol Regulatory Element Binding Protein 1
Diet
Amino Acids
Lipogenesis
Biomarkers
Metabolites
Proline
Arginine
Genotype
Modulation
Morbidity

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

Goudarzi, Maryam ; Koga, Takayuki ; Khozoie, Combiz ; Mac, Tytus D. ; Kang, Boo Hyon ; Fornace, Albert J. ; Peters, Jeffrey M. / PPARβ/δ modulates ethanol-induced hepatic effects by decreasing pyridoxal kinase activity. In: Toxicology. 2013 ; Vol. 311, No. 3. pp. 87-98.
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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.",
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Goudarzi, M, Koga, T, Khozoie, C, Mac, TD, Kang, BH, Fornace, AJ & Peters, JM 2013, 'PPARβ/δ modulates ethanol-induced hepatic effects by decreasing pyridoxal kinase activity', Toxicology, vol. 311, no. 3, pp. 87-98. https://doi.org/10.1016/j.tox.2013.07.002

PPARβ/δ modulates ethanol-induced hepatic effects by decreasing pyridoxal kinase activity. / Goudarzi, Maryam; Koga, Takayuki; Khozoie, Combiz; Mac, Tytus D.; Kang, Boo Hyon; Fornace, Albert J.; Peters, Jeffrey M.

In: Toxicology, Vol. 311, No. 3, 05.09.2013, p. 87-98.

Research output: Contribution to journalArticle

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AU - Peters, Jeffrey M.

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AB - 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.

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Goudarzi M, Koga T, Khozoie C, Mac TD, Kang BH, Fornace AJ et al. PPARβ/δ modulates ethanol-induced hepatic effects by decreasing pyridoxal kinase activity. Toxicology. 2013 Sep 5;311(3):87-98. https://doi.org/10.1016/j.tox.2013.07.002