Supported by grants from the National Key R&D Program of China (2016YFF0101504 and 2016YFF0101500 to Z.G.S.), the National Science Foundation of China (81970364 and 81770053 to Z.G.S; 81970070 to X.J.Z; 81970011 to P.Z; 82070079 to Y.X.J; 82000600 to F.J.H), the Hubei Provincial Natural Science Foundation of China (2020CFB665 to Y.H), Henan Charity Federation-Hepatobiliary Care Fund (GDXZ2021005 to Y.H.) and the Fundamental Research Funds for the Central Universities (2042019kf0134 to Y.C.).

Potential conflict of interest: Nothing to report.

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Abstract

Background and Aims

NAFLD has become the most common liver disease worldwide but lacks a well-established pharmacological therapy. Here, we aimed to investigate the role of an E3 ligase SH3 domain-containing ring finger 2 (SH3RF2) in NAFLD and to further explore the underlying mechanisms.

Methods and Results

In this study, we found that SH3RF2 was suppressed in the setting of NAFLD across mice, monkeys, and clinical individuals. Based on a genetic interruption model, we further demonstrated that hepatocyte SH3RF2 deficiency markedly deteriorates lipid accumulation in cultured hepatocytes and diet-induced NAFLD mice. Mechanistically, SH3RF2 directly binds to ATP citrate lyase, the primary enzyme promoting cytosolic acetyl–coenzyme A production, and promotes its K48-linked ubiquitination-dependent degradation. Consistently, acetyl–coenzyme A was significantly accumulated in Sh3rf2-knockout hepatocytes and livers compared with wild-type controls, leading to enhanced de novo lipogenesis, cholesterol production, and resultant lipid deposition.

Conclusion

SH3RF2 depletion in hepatocytes is a critical aggravator for NAFLD progression and therefore represents a promising therapeutic target for related liver diseases.

Supporting Information

References

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Author names in bold designate shared co-first authorship.

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Volume74, Issue3

September 2021

Pages 1319-1338

Hepatocyte SH3RF2 Deficiency Is a Key Aggravator for NAFLD

Abstract

Background and Aims

Methods and Results

Conclusion

Supporting Information

References

Citing Literature

References

Information

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Hepatocyte SH3RF2 Deficiency Is a Key Aggravator for NAFLD

Abstract

Background and Aims

Methods and Results

Conclusion

Supporting Information

References

Citing Literature

References

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