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

doi:10.1016/j.freeradbiomed.2021.05.032

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 journal › Article › peer-review

5 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 language	English
Pages (from-to)	90-100
Number of pages	11
Journal	Free Radical Biology and Medicine
Volume	172
DOIs	https://doi.org/10.1016/j.freeradbiomed.2021.05.032
State	Published - Aug 20 2021

Bibliographical note

Funding Information:
We thank the Markey Cancer Center Research Communications Office for editorial support and manuscript preparation. We also thank the Biostatistics and Bioinformatics Shared Resource Facility, the Biospecimen Procurement and Translational Pathology Shared Resource Facility, and the Flow Cytometry and Immune Monitoring Shared Resource Facility of the University of Kentucky Markey Cancer Center. This work was supported by the National Cancer Institute (R01 DK048498 and P30 CA177558).

Funding Information:
We thank the Markey Cancer Center Research Communications Office for editorial support and manuscript preparation. We also thank the Biostatistics and Bioinformatics Shared Resource Facility, the Biospecimen Procurement and Translational Pathology Shared Resource Facility, and the Flow Cytometry and Immune Monitoring Shared Resource Facility of the University of Kentucky Markey Cancer Center. This work was supported by the National Cancer Institute ( R01 DK048498 and P30 CA177558 ).

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)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.freeradbiomed.2021.05.032

Cite this

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title = "Ketogenesis alleviates TNFα-induced apoptosis and inflammatory responses in intestinal cells",

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.",

keywords = "Colorectal cancer, Crohn's disease, HMGCS2, Inflammatory bowel disease, Intestinal cells, Ketogenesis, TNFα, Ulcerative colitis",

author = "Kim, {Ji Tae} and Napier, {Dana L.} and Jinhwan Kim and Chang Li and Lee, {Eun Y.} and Weiss, {Heidi L.} and Qingding Wang and Evers, {B. Mark}",

note = "Funding Information: We thank the Markey Cancer Center Research Communications Office for editorial support and manuscript preparation. We also thank the Biostatistics and Bioinformatics Shared Resource Facility, the Biospecimen Procurement and Translational Pathology Shared Resource Facility, and the Flow Cytometry and Immune Monitoring Shared Resource Facility of the University of Kentucky Markey Cancer Center. This work was supported by the National Cancer Institute (R01 DK048498 and P30 CA177558). Funding Information: We thank the Markey Cancer Center Research Communications Office for editorial support and manuscript preparation. We also thank the Biostatistics and Bioinformatics Shared Resource Facility, the Biospecimen Procurement and Translational Pathology Shared Resource Facility, and the Flow Cytometry and Immune Monitoring Shared Resource Facility of the University of Kentucky Markey Cancer Center. This work was supported by the National Cancer Institute ( R01 DK048498 and P30 CA177558 ). Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

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AU - Kim, Ji Tae

AU - Napier, Dana L.

AU - Kim, Jinhwan

AU - Li, Chang

AU - Lee, Eun Y.

AU - Weiss, Heidi L.

AU - Wang, Qingding

AU - Evers, B. Mark

N1 - Funding Information: We thank the Markey Cancer Center Research Communications Office for editorial support and manuscript preparation. We also thank the Biostatistics and Bioinformatics Shared Resource Facility, the Biospecimen Procurement and Translational Pathology Shared Resource Facility, and the Flow Cytometry and Immune Monitoring Shared Resource Facility of the University of Kentucky Markey Cancer Center. This work was supported by the National Cancer Institute (R01 DK048498 and P30 CA177558). Funding Information: We thank the Markey Cancer Center Research Communications Office for editorial support and manuscript preparation. We also thank the Biostatistics and Bioinformatics Shared Resource Facility, the Biospecimen Procurement and Translational Pathology Shared Resource Facility, and the Flow Cytometry and Immune Monitoring Shared Resource Facility of the University of Kentucky Markey Cancer Center. This work was supported by the National Cancer Institute ( R01 DK048498 and P30 CA177558 ). Publisher Copyright: © 2021 Elsevier Inc.

PY - 2021/8/20

Y1 - 2021/8/20

N2 - 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.

AB - 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.

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KW - TNFα

KW - Ulcerative colitis

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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