Novel role of xanthine oxidase-dependent H2O2 production in 12/15-lipoxygenase-mediated de novo lipogenesis, triglyceride biosynthesis and weight gain

Suresh Govatati; Prahalathan Pichavaram; Arul M Mani; Raj Kumar; Deepti Sharma; Ari Dienel; Sunita Meena; Michelle A Puchowicz; Edwards A Park; Gadiparthi N Rao

doi:10.1016/j.redox.2021.102163

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Novel role of xanthine oxidase-dependent H2O2 production in 12/15-lipoxygenase-mediated de novo lipogenesis, triglyceride biosynthesis and weight gain

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Novel role of xanthine oxidase-dependent H2O2 production in 12/15-lipoxygenase-mediated de novo lipogenesis, triglyceride biosynthesis and weight gain

Suresh Govatati, Prahalathan Pichavaram, Arul M Mani, Raj Kumar, Deepti Sharma, Ari Dienel, Sunita Meena, Michelle A Puchowicz, Edwards A Park and Gadiparthi N Rao

Redox biology, Vol.47, 102163

11/2021

DOI: 10.1016/j.redox.2021.102163

PMCID: PMC8577505

PMID: 34655995

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Abstract

12/15-lipoxygenase (12/15-LOX) plays an essential role in oxidative conversion of polyunsaturated fatty acids into various bioactive lipid molecules. Although 12/15-LOX's role in the pathophysiology of various human diseases has been well studied, its role in weight gain is controversial and poorly clarified. Here, we demonstrated the role of 12/15-LOX in high-fat diet (HFD)-induced weight gain in a mouse model. We found that 12/15-LOX mediates HFD-induced de novo lipogenesis (DNL), triglyceride (TG) biosynthesis and the transport of TGs from the liver to adipose tissue leading to white adipose tissue (WAT) expansion and weight gain via xanthine oxidase (XO)-dependent production of H2O2. 12/15-LOX deficiency leads to cullin2-mediated ubiquitination and degradation of XO, thereby suppressing H2O2 production, DNL and TG biosynthesis resulting in reduced WAT expansion and weight gain. These findings infer that manipulation of 12/15-LOX metabolism may manifest a potential therapeutic target for weight gain and obesity. Highlights • 12/15-LOX-12(S)-HETE axis via activation of CREB-Egr1 enhances TG biosynthesis. • 12/15-LOX-12(S)-HETE axis via activation of SREBP1c triggers DNL. • H2O2 mediates 12/15-LOX-12(S)-HETE axis-induced DNL and TG biosynthesis. • 12/15-LOX via TG biosynthesis leads to WAT expansion and body weight gain. • Downstream to 12/15-LOX, H2O2-mediates WAT expansion and body weight gain.

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Title: Subtitle: Novel role of xanthine oxidase-dependent H2O2 production in 12/15-lipoxygenase-mediated de novo lipogenesis, triglyceride biosynthesis and weight gain
Creators: Suresh Govatati
Prahalathan Pichavaram
Arul M Mani
Raj Kumar
Deepti Sharma
Ari Dienel
Sunita Meena
Michelle A Puchowicz
Edwards A Park
Gadiparthi N Rao
Resource Type: Journal article
Publication Details: Redox biology, Vol.47, 102163
DOI: 10.1016/j.redox.2021.102163
PMID: 34655995
PMCID: PMC8577505
NLM abbreviation: Redox Biol
ISSN: 2213-2317
eISSN: 2213-2317
Grant note: DOI: 10.13039/100000050, name: NHLBI
Language: English
Electronic publication date: 09/16/2021
Date published: 11/2021
Academic Unit: Internal Medicine
Record Identifier: 9984535757002771

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