Circulating miRNAs associated with nonalcoholic fatty liver disease

Abstract

MicroRNAs (miRNAs) are secreted from cells as either protein bound or enclosed in extracellular vesicles. Circulating liver-derived miRNAs are modifiable by weight-loss or insulin-sensitizing treatments, indicating that they could be important biomarkers candidates for diagnosis, monitoring, and prognosis in NAFLD (non-alcoholic liver disease) and NASH (non-alcoholic steatohepatitis). Unfortunately, the non-invasive diagnosis of NASH and fibrosis remains a key challenge, which limits case finding. Current diagnostic guidelines therefore recommend liver biopsies, with risks of pain and bleeding for the patient and substantial healthcare costs. Here, we summarize mechanisms of RNA secretion, and review circulating RNAs associated with NAFLD and NASH for their biomarker potential. Few circulating miRNAs are consistently associated with NAFLD/NASH: miR-122, miR-21, miR-34a, miR-192, miR-193 and the miR-17-92 miRNA-cluster. The hepatocyte-enriched miRNA-122 is consistently increased in NAFLD and NASH but decrease in liver cirrhosis. Circulating miR-34a, part of an existing diagnostic algorithm for NAFLD, and miR-21 are consistently increased in NAFLD and NASH. MiR-192 appears to be prominently upregulated in NASH compared with NAFDL, whereas miR-193 was reported able to distinguish NASH from fibrosis. Various members of miRNA cluster miR-17-92 are reported associated with NAFLD and NASH, although with less consistency. Several other circulating miRNAs have been reported associated with fatty liver in few studies, indicating the existence of more circulating miRNAs with relevant as diagnostic markers for NAFLD or NASH. Thus, circulating miRNAs show potential as biomarkers of fatty liver disease, but more information about phenotype specificity and longitudinal regulation is needed.

Circulating microRNA as Biomarkers for Gestational Diabetes Mellitus—A Systematic Review and Meta-Analysis

“…However, no clear tendency can be seen across the studies, and therefore miR-122 is estimated to have little to no correlation with the development of GDM. Circulating miR-122, being released from hepatocytes during impaired glucose tolerance and in states of fatty liver disease [ 62 ], is an independent predictor of progression from impaired glucose tolerance to Type 2 diabetes [ 63 ]. However, data for patients with GDM regarding miR-122 display considerable heterogeneity, which cannot be explained by ethnicity, degree of obesity, biofluid material or different use of reference genes ( Supplementary Materials ).…”

“…miR-122 in circulation was not associated overall with a GDM diagnosis ( Figure 5 D), although this was reported to be associated with Type 2 diabetes [ 63 , 69 ] with hepatic steatosis [ 62 ] and the metabolic syndrome [ 87 ].…”

Mesenchymal stem cell‐derived extracellular vesicles in treatment against renal fibrosis

“…It has recently been suggested that autophagy may be linked to the activity of MSCs 19‐21 . Current studies have found that miRNA‐122 increases the levels of fibrotic factors such as collagen 1α1, collagen 1α2 and transforming growth factorβ1 (TGFβ1) in non‐alcoholic fatty liver disease cell models, thereby increasing the occurrence of fibrosis 22,23 . Administration of miRNA‐122 inhibitors reduces TGFβ‐induced key fibrotic signalling pathways, promotes collagen synthesis and stimulates fibrin production, leading to the accumulation of fibroblasts and extracellular matrix (ECM) in hypertension and cardiovascular disease 24,25 …”

“…[19][20][21] Current studies have found that miRNA-122 increases the levels of fibrotic factors such as collagen 1α1, collagen 1α2 and transforming growth factorβ1 (TGFβ1) in non-alcoholic fatty liver disease cell models, thereby increasing the occurrence of fibrosis. 22,23 Administration of miRNA-122 inhibitors reduces TGFβ-induced key fibrotic signalling pathways, promotes collagen synthesis and stimulates fibrin production, leading to the accumulation of fibroblasts and extracellular matrix (ECM) in hypertension and cardiovascular disease. 24,25 Li et al showed that MSC treatment improved damaged kidney structure and reduced RF by inhibiting autophagy and interfering with the mammalian target of rapamycin (mTOR) signalling pathway.…”

Extracellular microRNAs in Relation to Weight Loss—A Systematic Review and Meta-Analysis

“…Multiple studies have investigated the circulating levels of specific miRNA species in relation to obesity and comorbidities (reviewed in [8][9][10][11]). It has become apparent that the level of some miRNAs could be affected by intervention-driven weight loss [7,12].…”