Sirtuin-6 in Hepatic Fibrosis: Does Cell Type Matter?

Nonalcoholic fatty liver disease is a common metabolic disorder estimated to affect 25% of adults globally., Nonalcoholic steatohepatitis (NASH), a more severe and advanced stage of nonalcoholic fatty liver disease, leads to hepatocyte damage, fibrosis, cirrhosis, and eventually liver failure. NASH progression has also been linked to the development of hepatocellular carcinoma, diabetes, and cardiovascular disorders. Although the understanding of NASH pathogenesis has come a long way in the last 2 decades,,, the mechanism of NASH progression remains incompletely understood.

The current view holds that obesity-induced excessive accumulation of hepatic lipids causes inflammation, characterized by release of inflammatory cytokines, such as transforming growth factor (TGF)-β. TGF-β pathway activation promotes transcription of numerous target genes including fibrogenesis genes, such as ACTA2, COL1A1, and COL3A1. The resultant inflammatory milieu stimulates transformation of quiescent hepatic stellate cells into activated hepatic stellate cells that produce excess collagen to promote fibrosis, resulting in cirrhosis and liver failure. Thus, preventing or reversing fibrosis is a key factor to control the morbidity and mortality associated with NASH.

The study by Zhong et al published in this issue of Cellular and Molecular Gastroenterology and Hepatology identifies a novel key player in the progression of NASH. They discovered that the expression of the NAD-dependent deacetylase/deacylase,, Sirtuin 6 (Sirt-6), is reduced in patients with NASH and murine model of NASH. Moreover, Sirt-6-deficient mice fed a Western diet had increased hepatic injury, inflammation, and fibrosis, whereas transgenic mice with overexpression of Sirt-6 were protected. Mechanistically, they show that Sirt-6 negatively regulated the TGFβ/SMAD3 signaling; the loss of Sirt-6 in hepatic stellate cells was associated with a gain of SMAD3 phosphorylation (Figure 1). Using in vitro experiments with both mice and human hepatic stellate cell lines, the authors further confirmed that overexpression of Sirt-6 inhibits SMAD3 activation. Finally, they showed Sirt-6 deficiency led to increased SMAD3 acetylation in hepatic stellate cells (Figure 1).

Figure 1

The role of Sirt-6 in NASH progression. Schematic diagram depicting the role of Sirt-6 in normal and NASH liver. (A) In normal liver, Sirt-6 prevents phosphorylation and acetylation of SMAD3, thus inhibiting inflammation, fibrosis, and steatosis. (B) In NASH liver, Sirt-6 deficiency leads to increased phosphorylation and acetylation of SMAD3 resulting in increased inflammation and fibrosis. Ac, acetylation; ECM, extra cellular matrix; P, phosphorylation; SEC, sinusoidal endothelial cells.

While prior work, had demonstrated that Sirt-6 deficiency in hepatocytes accelerated lipid deposition and resulted in fibrosis, in the current manuscript, the authors discovered a novel role for Sirt-6 as an anti-inflammatory and antifibrotic molecule in hepatic stellate cells. Although activated hepatic stellate cells are the primary source of myofibroblasts in NASH and thus key drivers of fibrosis, the mechanistic knowledge regarding their activation in the context of NASH is still incomplete. The finding of Zhong et al that Sirt-6 regulates hepatic stellate cell activation via modulation of TGFβ/SMAD3 signaling to regulate fibrosis development in NASH is an important piece to the puzzle that promises to help in the development of novel treatment modalities to block the progression of or even reverse the course of fibrosis.

There are a few limitations in this study that should be the topic of future investigations. First, it is not yet known what causes the reduction of Sirt-6 expression in NASH. Second, it would be interesting to see the long-term effects of Sirt-6 deletion in hepatic stellate cells. Sirt-6 ablation in the liver has widespread effects on hepatocytes, cholangiocytes, and Kupffer cells. If activation of hepatic stellate cells is the predominant phenotype associated with NASH progression, then conditionally activating Sirt-6 in hepatic stellate cells might be able to reverse disease phenotypes in the other cell types.

In conclusion, Zhong et al have elegantly demonstrated the role of Sirt-6 in fibrosis progression by regulation of TGFβ/SMAD3 signaling in hepatic stellate cells. Thus, Sirt-6 represent a potential target for the treatment of NASH based on its role as an antifibrotic molecule. Additional studies are needed to improve the understanding of the interaction among SMAD3 and Sirt-6 in hepatic stellate cells and develop selective activators of Sirt-6 as a potential therapy for NASH.