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. 2023 Jul;43(7):1473-1485.
doi: 10.1111/liv.15578. Epub 2023 Apr 23.

Detrimental role of SIX1 in hepatic lipogenesis and fibrosis of non-alcoholic fatty liver disease

Xiaoliang Gao  1 , Yi Chu  2 , Weijie Wang  1 , Wenjiao Li  1 , Wenyao Zhang  1 , Jiayi Cao  1   3 , Xin Fu  1 , Hui Liu  1   3 , Di Chen  1 , Daiming Fan  1 , Yongzhan Nie  1
Affiliations

Detrimental role of SIX1 in hepatic lipogenesis and fibrosis of non-alcoholic fatty liver disease

Xiaoliang Gao et al. Liver Int. 2023 Jul.

Abstract

Background and aims: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Aberrant lipid metabolism and accumulation of extracellular matrix proteins are hallmarks of the disease, but the underlying mechanisms are largely unknown. This study aims to elucidate the key role of sine oculis homeobox homologue 1 (SIX1) in the development of NAFLD.

Methods: Alb-Cre mice were administered the AAV9 vector for SIX1 liver-specific overexpression or knockdown. Metabolic disorders, hepatic steatosis, and inflammation were monitored in mice fed with HFHC or MCD diet. High throughput CUT&Tag analysis was employed to investigate the mechanism of SIX1 in diet-induced steatohepatitis.

Results: Here, we found increased SIX1 expression in the livers of NAFLD patients and animal models. Liver-specific overexpression of SIX1 using adeno-associated virus serotype 9 (AAV9) provoked more severe inflammation, metabolic disorders, and hepatic steatosis in the HFHC or MCD-induced mice model. Mechanistically, we demonstrated that SIX1 directly activated the expression of liver X receptor α (LXRα) and liver X receptor β (LXRβ), thus inducing de novo lipogenesis (DNL). In addition, our results also illustrated a critical role of SIX1 in regulating the TGF-β pathway by increasing the levels of type I and II TGF-β receptor (TGFβRI/TGFβRII) in hepatic stellate cells (HSCs). Finally, we found that liver-specific SIX1 deficiency could ameliorate diet-induced NAFLD pathogenesis.

Conclusion: Our findings suggest a detrimental function of SIX1 in the progression of NAFLD. The direct regulation of LXRα/β and TGF-β signalling by SIX1 provides a new regulatory mechanism in hepatic steatosis and fibrosis.

Keywords: TGF-β signalling pathway; hepatic lipogenesis; liver fibrosis; non-alcoholic fatty liver disease; sine oculis homeobox homologue 1.

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References

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