Bariatric Surgery Associates with Nonalcoholic Steatohepatitis/Hepatocellular Carcinoma Amelioration via SPP1 Suppression

Abstract

Nonalcoholic steatohepatitis (NASH) is one of the most common chronic liver diseases worldwide and no effective drugs or treatments have been approved for disease management. Recently, bariatric surgery (BS) is considered to be a novel disease-modifying therapy for NASH and liver metabolic diseases, according to clinical follow-up studies. Despite the revealment of physiopathological alterations, underlying mechanisms and key factors remain indeterminate. This study included multiple bulk RNA-sequencing datasets to investigate transcriptome variation in one-year follow-up BS and diet management (Diet) NASH patients’ liver biopsies. Liver functions, fibrosis, and carcinogenesis were predicted in liver samples via hallmark-based function enrichment analysis. Key factors generated from multi-dataset comparison were further assessed with hepatocellular carcinoma (HCC) progression and prognosis. BS leads to active gene expression alterations in NASH liver in comparison to diet management (Diet). Both approaches reduce cell stress and immune response, whereas BS contributes to higher metabolic levels and lower apoptosis levels. The macrophage infiltration, adipose accumulation, and fibroblast activation were revealed to be lower in post-BS NASH livers, further demonstrating positive correlations mutually. Seven key genes (MNDA, ALOX5AP, PECAM1, SPP1, CD86, FGF21, CSTA) were screened out as potential macrophage-associated and carcinogenetic factors suppressed by BS. SPP1 was identified as a crucial factor participating in BS intervened NASH-HCC progression. This study determined that BS exerts potentially superior protective functions in NASH livers compared to diet management. SPP1 may serve as a novel factor to study the functionalities of BS on NASH patients.