LARP1 drives steatosis to hepatocellular carcinoma progression in MASH mouse models

Background: This study focuses on the role of an RNA binding protein, La-related protein 1 or LARP1 in progression of metabolic dysfunction–associated steatotic liver disease (MASLD). A knockout mouse model of the S-adenosylmethionine (SAMe) synthetic enzyme, methionine adenosyltransferase 1A (Mat1a-KO) spontaneously develops MASH and progresses to HCC. We discovered that LARP1 is strongly induced in Mat1a KO during the MASH stage (Ramani 2022, PMC8766892). RNA‑sequencing from LARP1‑overexpressing liver cancer cells and from Larp1‑silenced Mat1a KOs revealed that LARP1 regulates mRNAs controlling key metabolic pathways, including peroxisomal β‑oxidation (Sirtuin 5, SIRT5), aerobic glycolysis (c‑MYC), and oxidative phosphorylation/mitochondrial ribosomal proteins (MRPL13, MRPL50, MRPL59). This dataset is bulk RNA sequencing data from the above studies.  Our findings from RNA sequencing reveal a novel role for LARP1 in regulating metabolic pathways associated with MASLD progression through its dysregulation of key mRNAs involved in these pathways.

Methods
Experiment 1: Total RNA from human Huh7 liver cancer cells overexpressing an empty vector (EV) or a LARP1 vector was subject to polyribosome profiling to separate the actively translating ribosomal fraction and the non-translating fraction (NTR). The NTR and polysome fractions from EV or LARP1 OV groups was submitted for RNA sequencing (BGI Americas Inc.) and Poisson distribution and DEGseq2 analysis was performed on the same using human reference (GCF_000001405.38_GRCh38.p12).

Experiment 2: Total RNA was isolated from the livers of WT (CAS), Mat1a KO, and Mat1a KO mice injected with a Larp1 CRISPR silencing vector (Larp1 si). Bulk RNA sequencing was performed as in experiment 1 and Poisson distribution and DEGseq2 analysis was performed by using mouse reference (Mus_musculus_NCBI_GCF_000001635.27_GRCm39).