Role of LncSNHG5 in MAFLD: Mechanisms of Arid1a K391 lactylation and lipid accumulation.

INTRODUCTION

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common chronic liver condition marked by abnormal lipid metabolism.

OBJECTIVES

Small nucleolar RNA host gene 5 (SNHG5) is involved in the regulation of cell proliferation and apoptosis and was previously identified as a profibrotic factor in liver fibrosis. However, its role in MAFLD remains unclear. This study aimed to elucidate the contribution of SNHG5 to MAFLD progression.

METHODS AND

RESULTS

SNHG5 expression was markedly elevated during MAFLD progression, whereas SNHG5 inhibition suppressed lipid accumulation. Transcriptomic sequencing of primary hepatocytes overexpressing SNHG5 demonstrated significant downregulation of monocarboxylate transporter 1 (MCT1), a key lactate transporter. Integrated lactyl-proteomic and proteomic analyses further revealed that SNHG5 overexpression promoted lactylation of the non-histone protein AT-rich interaction domain 1A (Arid1a) at K391, thereby driving excessive lipid accumulation. Acyltransferase assays indicated that both P300 and HBO1 participated in SNHG5-mediated Arid1a lactylation. In vivo, hepatocyte-specific SNHG5 knockout markedly attenuated hepatic lipid accumulation and MAFLD progression, whereas simultaneous hepatocyte-specific deletion of SNHG5 and MCT1 restored lipid accumulation compared with SNHG5-deficient mice.

CONCLUSION

SNHG5 promotes lipid accumulation and MAFLD progression through induction of MCT1-mediated Arid1a K391 lactylation.