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However, the role and mechanism of TM6SF2 E167K variant during MASLD progression are not yet fully understood.Methods: The &lt;i&gt;Tm6sf2&lt;sup&gt;167K&lt;\/sup&gt;&lt;\/i&gt; knock-in (KI) mice were subjected to high-fat diet (HFD). Hepatic lipid levels of &lt;i&gt;Tm6sf2&lt;sup&gt;167K&lt;\/sup&gt;&lt;\/i&gt; KI mice were detected by lipidomics analysis. Thin-layer chromatography (TLC) was used to measure the newly synthesized triglyceride (TG) and phosphatidylcholine (PC).Results: The TM6SF2 E167K variant significantly aggravated hepatic steatosis and injury in HFD-induced mice. Decreased polyunsaturated PC level and increased polyunsaturated TG level were found in liver tissue of HFD-induced &lt;i&gt;Tm6sf2&lt;sup&gt;167K&lt;\/sup&gt;&lt;\/i&gt; KI mice. Mechanistic studies demonstrated that the TM6SF2 E167K variant increased the interaction between TM6SF2 and PNPLA3, and impaired PNPLA3-mediated transfer of polyunsaturated fatty acids (PUFAs) from TG to PC. The TM6SF2 E167K variant increased the level of fatty acid-induced malondialdehyde and reactive oxygen species, and decreased fatty acid-downregulated cell membrane fluidity. Additionally, the TM6SF2 E167K variant decreased the level of hepatic PC containing C18:3, and dietary supplementation of PC containing C18:3 significantly attenuated the TM6SF2 E167K-induced hepatic steatosis and injury in HFD-fed mice.Conclusions: The TM6SF2 E167K variant could promote its interaction with PNPLA3 and inhibit PNPLA3-mediated transfer of PUFAs from TG to PC, resulting in the hepatic steatosis and injury during MASLD progression. PC containing C18:3 could act as a potential therapeutic supplement for MASLD patients carrying the TM6SF2 E167K variant.<\/jats:p>","DOI":"10.3350\/cmh.2024.0268","type":"journal-article","created":{"date-parts":[[2024,7,26]],"date-time":"2024-07-26T04:36:34Z","timestamp":1721968594000},"page":"863-882","update-policy":"https:\/\/doi.org\/10.3350\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["TM6SF2 E167K variant decreases PNPLA3-mediated PUFA transfer to promote hepatic steatosis and injury in 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