Ketogenesis alleviates TNFα-induced apoptosis and inflammatory responses in intestinal cells

Ji Tae Kim, Dana L. Napier, Jinhwan Kim, Chang Li, Eun Y. Lee, Heidi L. Weiss, Qingding Wang, B. Mark Evers

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

The disturbance of strictly regulated self-regeneration in mammalian intestinal epithelium is associated with various intestinal disorders, particularly inflammatory bowel diseases (IBDs). TNFα, which plays a critical role in the pathogenesis of IBDs, has been reported to inhibit production of ketone bodies such as β-hydroxybutyrate (βHB). However, the role of ketogenesis in the TNFα-mediated pathological process is not entirely known. Here, we showed the regulation and role of HMGCS2, the rate-limiting enzyme of ketogenesis, in TNFα-induced apoptotic and inflammatory responses in intestinal epithelial cells. Treatment with TNFα dose-dependently decreased protein and mRNA expression of HMGCS2 and its product, βHB production in human colon cancer cell lines HT29 and Caco2 cells and mouse small intestinal organoids. Moreover, the repressed level of HMGCS2 protein was found in intestinal epithelium of IBD patients with Crohn's disease and ulcerative colitis as compared with normal tissues. Furthermore, knockdown of HMGCS2 enhanced and in contrast, HMGCS2 overexpression attenuated, the TNFα-induced apoptosis and expression of pro-inflammatory chemokines (CXCL1-3) in HT29, Caco2 cells and DLD1 cells, respectively. Treatment with βHB or rosiglitazone, an agonist of PPARγ, which increases ketogenesis, attenuated TNFα-induced apoptosis in the intestinal epithelial cells. Finally, HMGCS2 knockdown enhanced TNFα-induced reactive oxygen species (ROS) generation. In addition, hydrogen peroxide, the major ROS contributing to intestine injury, decreased HMGCS2 expression and βHB production in the intestinal cells and mouse organoids. Our findings demonstrate that increased ketogenesis attenuates TNFα-induced apoptosis and inflammation in intestinal cells, suggesting a protective role for ketogenesis in TNFα-induced intestinal pathologies.

Original languageEnglish
Pages (from-to)90-100
Number of pages11
JournalFree Radical Biology and Medicine
Volume172
DOIs
StatePublished - Aug 20 2021

Bibliographical note

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

  • Colorectal cancer
  • Crohn's disease
  • HMGCS2
  • Inflammatory bowel disease
  • Intestinal cells
  • Ketogenesis
  • TNFα
  • Ulcerative colitis

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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