Higher intestinal and circulatory lactate associated NOX2 activation leads to an ectopic fibrotic pathology following microcystin co-exposure in murine fatty liver disease

Sutapa Sarkar, Punnag Saha, Ratanesh K. Seth, Ayan Mondal, Dipro Bose, Diana Kimono, Muayad Albadrani, Avik Mukherjee, Dwayne E. Porter, Geoff I. Scott, Shuo Xiao, Bryan Brooks, John Ferry, Mitzi Nagarkatti, Prakash Nagarkatti, Saurabh Chatterjee

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Clinical studies implicated an increased risk of intestinal fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Our previous studies have shown that microcystin-LR (MC-LR) exposure led to altered gut microbiome and increased abundance of lactate producing bacteria and intestinal inflammation in underlying NAFLD. This led us to further investigate the effects of the MC-LR, a PP2A inhibitor in activating the TGF-β fibrotic pathway in the intestines that might be mediated by increased lactate induced redox enzyme NOX2. Exposure to MC-LR led to higher lactate levels in circulation and in the intestinal content. The higher lactate levels were associated with NOX2 activation in vivo that led to increased Smad2/3-Smad4 co-localization and high alpha-smooth muscle actin (α-SMA) immunoreactivity in the intestines. Mechanistically, primary mouse intestinal epithelial cells treated with lactate and MC-LR separately led to higher NOX2 activation, phosphorylation of TGFβR1 receptor and subsequent Smad 2/3-Smad4 co-localization inhibitable by apocynin (NOX2 inhibitor), FBA (a peroxynitrite scavenger) and DMPO (a nitrone spin trap), catalase and superoxide dismutase. Inhibition of NOX2-induced redox signaling also showed a significant decrease in collagen protein thus suggesting a strong redox signaling induced activation of an ectopic fibrotic manifestation in the intestines. In conclusion, the present study provides mechanistic insight into the role of microcystin in dysbiosis-linked lactate production and subsequently advances our knowledge in lactate-induced NOX2 exacerbation of the cell differentiation and fibrosis in the NAFLD intestines.

Original languageEnglish (US)
Article number108854
JournalComparative Biochemistry and Physiology Part - C: Toxicology and Pharmacology
Volume238
DOIs
StatePublished - Dec 2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology
  • Aquatic Science
  • Animal Science and Zoology
  • Toxicology
  • Cell Biology
  • Health, Toxicology and Mutagenesis

Keywords

  • Dysbiosis
  • Fibrosis
  • Lactate
  • MC-LR
  • NAFLD
  • NOX2
  • PP2A inhibitor
  • Peroxynitrite

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