Effects of TMEM55B deficiency on hepatic gene expression of Western diet-fed male mice

Transmembrane protein 55B (TMEM55B) is a lysosomal protein that modulates lysosome position and function. We examined the impact of TMEM55B deficiency on mitochondrial function and the development of Metabolic Dysfunction Associated with Steatohepatitis (MASH). We found that several genes implicated in mitochondria function including mitophagy regulator Prkn (p=1.11e-10), and Immp2i (p=1.29e-22) and Sugct (p=8.82e-10) were downregulated in the livers of male mice treated with Tmem55b ASO compared to NTC ASO. In additon, the RNAseq analysis of 4-week Tmem55b vs. NTC ASO treatment demonstrated a functional enrichment of upregulated genes involved in cell adhesion (Flrt2, Egfl7, Col8a1, Pkp3, Pcdh17, Mcam) in the liver. Taken together, our data suggested that loss of TMEM55B accelerates diet-induced MASLD onset and progression in mice through impaired mitochondrial function. Overall design: To investigate the role of TMEM55B in the onset and progress of MASLD, male 6-7 week-old C57BL/6J mice were treated with Tmem55b (N=4) or non-targeting control (N=4) ASOs at a dose of 25 mg/ kg body weight/wk and fed Western diet (43% fat, 0.2% cholesterol, Harlan Laboratories, Madison, WI) for 4 weeks. Total RNA was extracted from livers, checked for quality on a Bioanalyzer, and made into polyA-selected, strand-specific RNA-seq libraries for 150 bp paired-end sequencing on Illumina NovaSeq machines.