<h4>Background & aims</h4>Transmembrane protein 41B (TMEM41B) and vacuolar membrane protein 1 (VMP1) are endoplasmic reticulum (ER) scramblases whose roles in hepatic lipoprotein secretion and autophagy in metabolic-associated steatotic liver disease (MASLD) remain unclear.<h4>Methods</h4>We undertook lipidomic and functional studies in liver- and hepatocyte-specific Tmem41b knockout (KO) mice; Tmem41b knock-in (KI) mice, Tmem41b/Vmp1 double KO (DKO); Tmem41b KO/Vmp1 KI, and Vmp1 KO/Tmem41b KI mice.<h4>Results</h4>TMEM41B protein levels decreased in the livers of human subjects with MASLD. The gene discussed is VMP1; the disease is metabolic dysfunction-associated steatotic liver disease.