Related Experiment Video
Updated: Sep 24, 2025
Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis
Published on: March 11, 2017
Impaired reciprocal regulation between SIRT6 and TGF-β signaling in fatty liver
Xiyan Xiang1,2, Kazufumi Ohshiro1, Sobia Zaidi1,2
1The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA.
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.
Insights
Dysregulated transforming growth factor-beta (TGF-β) signaling and reduced SIRT6 protein contribute to fatty liver disease. A novel regulatory loop between SIRT6 and SPTBN1 may explain susceptibility to liver pathologies.
Area of Science:
- Hepatology
- Molecular Biology
- Biochemistry
Background:
- Dysregulated transforming growth factor-beta (TGF-β) signaling is implicated in fibrotic liver disease and hepatocellular cancer (HCC), often co-occurring with fatty liver disease.
- SIRT6 plays a protective role by inhibiting TGF-β signaling and lipogenesis.
- The interplay between TGF-β signaling and SIRT6 in fatty liver disease remains unclear.
Purpose of the Study:
- To investigate the reciprocal regulation between TGF-β signaling and SIRT6 in the context of fatty liver disease.
- To elucidate the role of the SMAD3-SPTBN1 pathway in mediating TGF-β-induced SIRT6 expression.
- To explore the impact of SIRT6 on TGF-β signaling and lipogenesis in hepatocellular cancer cells.
Main Methods:
- Utilized a high-fat diet mouse model to induce fatty liver.
- Assessed liver pathology in wild-type versus TGF-β signaling-deficient mice (SPTBN1+/-).
- Investigated SIRT6 abundance, SMAD3 binding to the SIRT6 promoter, and the effects of SIRT6 manipulation in HCC cells.
Main Results:
- TGF-β signaling-deficient mice exhibited exacerbated fatty liver and reduced hepatic SIRT6 abundance.
- SMAD3 or SPTBN1 deficiency decreased SIRT6 expression and impaired TGF-β-induced SIRT6 transcription.
- SMAD3 bound to the SIRT6 promoter, indicating an SMAD3-SPTBN1 pathway's role in TGF-β-mediated SIRT6 induction.
- SIRT6 overexpression suppressed TGF-β-induced genes in HCC cells.
- SIRT6 manipulation affected sterol regulatory element-binding protein (SREBP) activity and SPTBN1 acetylation.
- SIRT6 overexpression impaired SREBP target gene induction in SPTBN1 heterozygous cells.
Conclusions:
- A novel regulatory loop between SIRT6 and SPTBN1 was identified.
- This loop represents a potential mechanism contributing to fatty liver susceptibility when TGF-β signaling is dysfunctional.
- Findings highlight the complex interplay between TGF-β, SIRT6, and lipogenesis in liver pathology.
More Related Videos
06:54Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
06:08Author Spotlight: Semi-Automated Isolation of the Stromal Vascular Fraction from Murine White Adipose Tissue Using a Tissue Dissociator
Published on: May 19, 2023
Related Concept Videos
01:16TGF - β Signaling Pathway
02:26NF-κB-dependent Signaling Pathway
NF-κB-dependent Signaling Mechanism
The...