LARP6 regulates the mRNA translation of fibrogenic genes in liver fibrosis.

Abstract

Metabolic syndrome and excessive alcohol consumption result in liver injury and fibrosis, which is characterized by increased collagen production by activated Hepatic Stellate Cells (HSCs). LARP6, an RNA-binding protein, was shown to facilitate collagen production. However, LARP6 expression and functionality as a regulator of fibrosis development in a disease relevant model remains elusive. By using snRNA-sequencing, we show that LARP6 is upregulated mainly in HSCs of liver fibrosis patients. Moreover, LARP6 knockdown in human HSCs suppresses fibrogenic gene expression. By integrating eCLIP analysis and ribosome profiling in HSCs, we show that LARP6 interacts with mature mRNAs comprising over 300 genes, including RNA structural elements within <i>COL1A1</i> , <i>COL1A2</i> , and <i>COL3A1</i> to regulate mRNA expression and translation. Furthermore, LARP6 knockdown in HSC attenuates fibrosis development in human liver spheroids. Altogether, our results suggest that targeting LARP6 in human HSCs may provide new strategies for anti-fibrotic therapy. LARP6 is upregulated in liver fibrosis, mainly in HSCs.LARP6 knockdown in human HSCs reduces liver fibrosis development.Of the hundreds of gene targets, LARP6 interacts most with collagen mRNAs.LARP6 regulates mRNA translation via interaction with 5'UTRs.