ABSTRACT
Non-alcoholic fatty liver disease (NAFLD) has become one of the most frequent chronic liver diseases worldwide in recent decades. Metabolic diseases like excessive blood glucose, central obesity, dyslipidemia, hypertension, and liver function abnormalities cause NAFLD. NAFLD significantly increases the likelihood of liver cancer, heart disease, and mortality, making it a leading cause of liver transplants. Non-alcoholic steatohepatitis (NASH) is a more advanced form of the disease that causes scarring and inflammation of the liver over time and can ultimately result in cirrhosis and hepatocellular carcinoma. In this review, we briefly discuss NAFLD's pathogenic mechanisms, their progression into NASH and afterward to NASH-related cirrhosis. It also covers disease epidemiology, metabolic mechanisms, glucose and lipid metabolism in the liver, macrophage dysfunction, bile acid toxicity, and liver stellate cell stimulation. Additionally, we consider the contribution of intestinal microbiota, genetics, epigenetics, and ecological factors to fibrosis progression and hepatocellular carcinoma risk in NAFLD and NASH patients.
ABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is a common liver disorder affecting a quarter of the global residents. Progression of NAFL into nonalcoholic steatohepatitis (NASH) may cause cirrhosis, liver cancer, and failure. Gut microbiota imbalance causes microbial components translocation into the circulation, triggering liver inflammation and NASH-related fibrosis. MicroRNAs (miRNAs) regulate gene expression via repressing target genes. Exosomal miRNAs are diagnostic and prognostic biomarkers for NAFL and NASH liver damage. Our work investigated the role of the gut microbiota in NAFLD pathogenesis via the lipopolysaccharide/toll-like receptor 4/Forkhead box protein O3 (LPS/TLR-4/FoxO3) pathway and certain miRNAs as noninvasive biomarkers for NAFL or its development to NASH. miRNA expression levels were measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in 50 NAFL patients, 50 NASH patients, and 50 normal controls. Plasma LPS, TLR-4, adiponectin, peroxisome proliferator-activated receptor γ (PPAR-γ), and FoxO3 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). In NAFL and NASH patients, miR-122, miR-128, FoxO3, TLR-4, LPS, and PPAR-γ were upregulated while miR-200, miR-298, miR-342, and adiponectin were downregulated compared with the normal control. The examined miRNAs might distinguish NAFL and NASH patients from the normal control using receiver operating characteristic analysis. Our study is the first to examine these miRNAs in NAFLD. Our findings imply that these are potentially promising biomarkers for noninvasive early NAFL diagnosis and NASH progression. Understanding the LPS/TLR-4/FoxO3 pathway involvement in NAFL/NASH pathogenesis may aid disease management.
Subject(s)
MicroRNAs , Non-alcoholic Fatty Liver Disease , Humans , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Lipopolysaccharides/pharmacology , Adiponectin/metabolism , Forkhead Box Protein O3/genetics , Forkhead Box Protein O3/metabolism , Peroxisome Proliferator-Activated Receptors/metabolism , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Structure-Activity Relationship , MicroRNAs/genetics , MicroRNAs/metabolism , Biomarkers/metabolism , Liver/metabolismABSTRACT
Retroviral envelope (env)-like sequences in 2 cultivated allotetraploid cottons and their diploid progenitors have been identified and characterized in this study. DNA sequence analysis reveals that these sequences are heterogeneous. The observed sequence diversity, however, seems to preserve coding information. This is evidenced by the detection of the transmembrane domain (TM), which is the most conserved feature of the divergent retroviral env genes. The high ratio of synonymous to nonsynonymous changes suggests that these sequences are evolving under purifying selection. Phylogenetic analysis shows that Gossypium sequences closely cluster with a lineage of plant endogenous retroviruses that have an env-like gene. These results provide evidence for the antiquity and the wide diversity of env-like sequences in the Gossypium genome.
