METTL1 promotes hepatic steatosis by mediating m7G modification of ALOX15B mRNA.

BACKGROUND

Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined by aberrant hepatic lipid accumulation, yet the regulatory mechanisms underlying this process remain incompletely understood. Although epitranscriptomic modifications have emerged as key regulators of hepatic lipid homeostasis, the role of N7-methylguanosine (m7G) modification in hepatic steatosis remains unclear.

METHODS

Histological and immunohistochemistry studies were used to assess lipid deposition in free fatty acids (FFAs)-incubated AML12 and HepG2 cells, high-fat diet (HFD)-fed mice, and human liver samples from MASLD patients. Stable overexpression and knockdown of methyltransferase like 1 (METTL1) were established to investigate the effects of METTL1 on m7G methylation and hepatocellular lipid metabolism. RNA-sequencing and RNA immunoprecipitation-quantitative-PCR (RIP-qPCR) analysis were performed to identify downstream molecular targets of METTL1.

RESULTS

METTL1 expression was significantly increased in fatty liver tissues from both human and mouse compared with corresponding controls. METTL1 knockdown markedly attenuated FFAs-induced lipid accumulation in hepatocytes, whereas METTL1 overexpression exacerbated this phenotype. Notably, enforced ALOX15B expression reversed the attenuation of hepatic lipid accumulation induced by METTL1 knockdown. Mechanistically, METTL1 enhances the stability of ALOX15B mRNA through depositing m7G modifications, thereby elevating ALOX15B protein levels, activating ERK1/2 pathway and promoting hepatic steatosis.

CONCLUSIONS

Our findings identify a METTL1-ALOX15B epitranscriptomic regulatory axis in which METTL1-dependent m7G modification of ALOX15B mRNA and promote hepatic steatosis, highlighting a potential therapeutic target for MASLD.