Impaired reciprocal regulation between SIRT6 and TGF-β signaling in fatty liver

Xiyan Xiang, The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA.
Kazufumi Ohshiro, The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA.
Sobia Zaidi, The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA.
Xiaochun Yang, The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA.
Krishanu Bhowmick, The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA.
Anil K. Vegesna, The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA.
David Bernstein, Division of Hepatology, Northwell Health and Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA.
James M. Crawford, Department of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA.
Bibhuti Mishra, The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA.
Patricia S. Latham, Department of Pathology, George Washington University, Washington, District of Columbia, USA.
Nancy R. Gough, The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA.
Shuyun Rao, The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA.
Lopa Mishra, The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA.

Document Type

Journal Article

Publication Date

6-1-2022

Journal

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Volume

36

Issue

6

DOI

10.1096/fj.202101518R

Keywords

NASH; SIRT6; TGF-β signaling; fatty liver

Abstract

Dysregulated transforming growth factor-beta (TGF-β) signaling contributes to fibrotic liver disease and hepatocellular cancer (HCC), both of which are associated with fatty liver disease. SIRT6 limits fibrosis by inhibiting TGF-β signaling through deacetylating SMAD2 and SMAD3 and limits lipogenesis by inhibiting SREBP1 and SREBP2 activity. Here, we showed that, compared to wild-type mice, high-fat diet-induced fatty liver is worse in TGF-β signaling-deficient mice (SPTBN1 ) and the mutant mice had reduced SIRT6 abundance in the liver. Therefore, we hypothesized that altered reciprocal regulation between TGF-β signaling and SIRT6 contributes to these liver pathologies. We found that deficiency in SMAD3 or SPTBN1 reduced SIRT6 mRNA and protein abundance and impaired TGF-β induction of SIRT6 transcripts, and that SMAD3 bound to the SIRT6 promoter, suggesting that an SMAD3-SPTBN1 pathway mediated the induction of SIRT6 in response to TGF-β. Overexpression of SIRT6 in HCC cells reduced the expression of TGF-β-induced genes, consistent with the suppressive role of SIRT6 on TGF-β signaling. Manipulation of SIRT6 abundance in HCC cells altered sterol regulatory element-binding protein (SREBP) activity and overexpression of SIRT6 reduced the amount of acetylated SPTBN1 and the abundance of both SMAD3 and SPTBN1. Furthermore, induction of SREBP target genes in response to SIRT6 overexpression was impaired in SPTBN1 heterozygous cells. Thus, we identified a regulatory loop between SIRT6 and SPTBN1 that represents a potential mechanism for susceptibility to fatty liver in the presence of dysfunctional TGF-β signaling.

Department

Pathology

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