TY - JOUR
T1 - Deletion of TRPC3 or TRPC6 fails to attenuate the formation of inflammation and fibrosis in non-alcoholic steatohepatitis
AU - Nishiyama, Kazuhiro
AU - Toyama, Chiemi
AU - Kato, Yuri
AU - Tanaka, Tomohiro
AU - Nishimura, Akiyuki
AU - Nagata, Ryu
AU - Mori, Yasuo
AU - Nishida, Motohiro
N1 - Funding Information:
We thank Professor Lutz Birnbaumer (NIEHS, Research Triangle Park, NC, U.S.A.) for the kind gift of TRPC3 KO and TRPC6 KO 129Sv strain mice. We appreciate the technical assistance from The Research Support Center, Research Center for Human Disease Modeling, Kyushu University Graduate School of Medical Sciences. This work was supported by Grants from JSPS KAKENHI (20K16008 to K.N., 20K15993 to Y.K., 19K16363 to T.T., 19K07085 to A.N., and 19H03383 to M.N.). This work was also supported by the Cooperative Study Program (19-213 to K.N.) of National Institute for Physiological Sciences.
Funding Information:
TRPC3 and TRPC6 are known to be activated by diacyl-In this study, we found that expression of TRPC3 is in-glycerol downstream of the muscarinic receptor.20) The mus-creased in mice fed with CDAHFD (Fig. 1A). In addition, carinic receptor has been reported to be associated with liver liver weights in TRPC3 KO mice fed with CDAHFD were fibrosis.21) However, we found that gene deletion of TRPC3 reduced compared with in WT mice fed with CDAHFD (Fig. or TRPC6 alone cannot significantly suppress the increased 2C). On the other hand, although the expression of TRPC6 expressions of inflammation and fibrosis markers in NASH was not increased in mice fed with CDAHFD, TRPC6 de-model. Other TRPCs might compensate for the functional ficiency suppressed the decrease in body weight and HDLC deficiency of TRPC3 or TRPC6. In fact, it has been reported (Figs. 2C, 3C). These results suggest that the physical status that the deletion of TRPC3 or TRPC6 alone is not protective in TRPC6 KO mice fed with CDAHFD was improved in against pressure overload-induced cardiac fibrosis, whereas comparison to WT mice fed with CDAHFD. However, liver their combined deletion is protective.22) Therefore, deletion of steatosis, inflammation and fibrosis were not significantly both TRPC3 and TRPC6 genes might suppress inflammation di*? erent among and WT, TRPC3 KO and TRPC6 KO mice and fibrosis in the NASH model. fed with CDAHFD (Figs. 4, 5). Both TRPC3 and TRPC6 are expressed in various tissues other than the liver. TRPC3 Acknowledgments We thank Professor Lutz Birnbaumer is highly expressed in the heart and blood vessels,6) and acts (NIEHS, Research Triangle Park, NC, U.S.A.) for the kind gift as a channel and sca*? old protein. We found that TRPC3 is of TRPC3 KO and TRPC6 KO 129Sv strain mice. We appre-involved in liver weight increase induced by CDAHFD inde-ciate the technical assistance from The Research Support Cen-pendent of inflammation and fibrosis. Thus, TRPC3 deficiency ter, Research Center for Human Disease Modeling, Kyushu in tissue(s) other than liver may indirectly contribute to liver University Graduate School of Medical Sciences. weight increase induced by CDAHFD feeding. In addition, This work was supported by Grants from JSPS KAKENHI TRPC6 is also expressed in various tissues such as kidney and (20K16008 to K.N., 20K15993 to Y.K., 19K16363 to T.T., lung,16–18) and it might be possible that deficient of TRPC6 in 19K07085 to A.N., and 19H03383 to M.N.). This work was these tissues indirectly led to the improvement of body weight also supported by the Cooperative Study Program (19-213 to loss. Food intakes were not significantly di*? erent among WT, K.N.) of National Institute for Physiological Sciences. TRPC3 KO and TRPC6 KO mice, but food intake of TRPC6 KO tended to be greater than WT and TRPC3 KO mice (Fig. Conflict of Interest The authors declare no conflict of 2B). A recent paper has suggested that TRPC6 deficiency interest.
Publisher Copyright:
© 2021 The Pharmaceutical Society of Japan
PY - 2021/3/1
Y1 - 2021/3/1
N2 - Non-alcoholic steatohepatitis (NASH) is a disease that has progressed from non-alcoholic fatty liver disease (NAFLD) and is characterized by inflammation and fibrosis. Two transient receptor potential canonical (TRPC) subfamily members, TRPC3 and TRPC6 (TRPC3/6), reportedly participate in the development of fibrosis in cardiovascular and renal systems. We hypothesized that TRPC3/6 may also participate in NASH fibrosis. We evaluated the effects of TRPC3 or TRPC6 functional deficiency in a NASH mouse model using choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Wild-type (WT) and TRPC3 or TRPC6 gene-deficient (KO) mice were fed with CDAHFD or standard diet for 6 weeks. The CDAHFD-induced body weight loss in TRPC6 KO mice was significantly lower compared with WT mice with CDAHFD. CDAHFD treatment significantly increased TRPC3 mRNA expression level and tissue weight in WT liver, which were suppressed in TRPC3 KO mice. However, either systemic deletion of TRPC3 or TRPC6 failed to attenuate liver steatosis, inflammation and fibrosis. These results imply that TRPC3 and TRPC6 are unlikely to be involved in liver dysfunction and fibrosis of NASH model mice.
AB - Non-alcoholic steatohepatitis (NASH) is a disease that has progressed from non-alcoholic fatty liver disease (NAFLD) and is characterized by inflammation and fibrosis. Two transient receptor potential canonical (TRPC) subfamily members, TRPC3 and TRPC6 (TRPC3/6), reportedly participate in the development of fibrosis in cardiovascular and renal systems. We hypothesized that TRPC3/6 may also participate in NASH fibrosis. We evaluated the effects of TRPC3 or TRPC6 functional deficiency in a NASH mouse model using choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Wild-type (WT) and TRPC3 or TRPC6 gene-deficient (KO) mice were fed with CDAHFD or standard diet for 6 weeks. The CDAHFD-induced body weight loss in TRPC6 KO mice was significantly lower compared with WT mice with CDAHFD. CDAHFD treatment significantly increased TRPC3 mRNA expression level and tissue weight in WT liver, which were suppressed in TRPC3 KO mice. However, either systemic deletion of TRPC3 or TRPC6 failed to attenuate liver steatosis, inflammation and fibrosis. These results imply that TRPC3 and TRPC6 are unlikely to be involved in liver dysfunction and fibrosis of NASH model mice.
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U2 - 10.1248/bpb.b20-00903
DO - 10.1248/bpb.b20-00903
M3 - Article
C2 - 33642551
AN - SCOPUS:85101818372
SN - 0918-6158
VL - 44
SP - 431
EP - 436
JO - Biological and Pharmaceutical Bulletin
JF - Biological and Pharmaceutical Bulletin
IS - 3
ER -