RESUMO

The knowledge on the genetic component of non-alcoholic fatty liver disease (NAFLD) has grown exponentially over the last 10 to 15 years. This review summarizes the current evidence and the latest developments in the genetics of NAFLD and non-alcoholic steatohepatitis (NASH) from the immune system's perspective. Activation of innate and or adaptive immune response is an essential driver of NAFLD disease severity and progression. Lipid and immune pathways are crucial in the pathophysiology of NAFLD and NASH. Here, we highlight novel applications of genomic techniques, including single-cell sequencing and the genetics of gene expression, to elucidate the potential involvement of NAFLD/NASH-risk alleles in modulating immune system cells. Together, our focus is to provide an overview of the potential involvement of the NAFLD/NASH-related risk variants in mediating the immune-driven liver disease severity and diverse systemic pleiotropic effects.

Assuntos

Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Alelos , Fígado/metabolismo , Neoplasias Hepáticas/genética , Imunidade

RESUMO

Nonalcoholic fatty liver disease (NAFLD) pathogenesis is explained by the complex relationship among diet and lifestyle-predisposing factors, the genetic variance of the nuclear and mitochondrial genome, associated phenotypic traits, and the yet not fully explored interactions with epigenetic and other environmental factors, including the microbiome. Despite the wealth of knowledge gained from molecular and genome-wide investigations in patients with NAFLD, the precise mechanisms that explain the variability of the histological phenotypes are not fully understood. Earlier studies of the gut microbiota in patients with NAFLD and nonalcoholic steatohepatitis (NASH) provided clues on the role of the fecal microbiome in the disease pathogenesis. Nevertheless, the composition of the gut microbiota does not fully explain tissue-specific mechanisms associated with the degree of disease severity, including liver inflammation, ballooning of hepatocytes, and fibrosis. The liver acts as a key filtration system of the whole body by receiving blood from the hepatic artery and the portal vein. Therefore, not only microbes would become entrapped in the complex liver anatomy but, more importantly, bacterial derived products that are likely to be potentially powerful stimuli for initiating the inflammatory response. Hence, the study of liver tissue microbiota offers the opportunity of changing the paradigm of host-NAFLD-microbial interactions from a "gut-centric" to a "liver-centric" approach. Here, we highlight the evidence on the role of liver tissue bacterial DNA in the biology of NAFLD and NASH. Besides, we provide evidence of metagenomic findings that can serve as the seed of further hypothesis-raising studies as well as can be leveraged to discover novel therapeutic targets.