The Role of Long Non-Coding RNAs (lncRNAs) in the Development and Progression of Fibrosis Associated with Nonalcoholic Fatty Liver Disease (NAFLD)

Abstract

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of conditions ranging from hepatic steatosis to inflammation (nonalcoholic steatohepatitis or NASH) with or without fibrosis, in the absence of significant alcohol consumption. The presence of fibrosis in NASH patients is associated with greater liver-related morbidity and mortality; however, the molecular mechanisms underlying the development of fibrosis and cirrhosis in NAFLD patients remain poorly understood. Long non-coding RNAs (lncRNAs) are emerging as key contributors to biological processes that are underpinning the initiation and progression of NAFLD fibrosis. This review summarizes the experimental findings that have been obtained to date in animal models of liver fibrosis and NAFLD patients with fibrosis. We also discuss the potential applicability of circulating lncRNAs to serve as biomarkers for the diagnosis and prognosis of NAFLD fibrosis. A better understanding of the role played by lncRNAs in NAFLD fibrosis is critical for the identification of novel therapeutic targets for drug development and improved, noninvasive methods for disease diagnosis.

LncRNAs Act as a Link between Chronic Liver Disease and Hepatocellular Carcinoma

“…HOTAIR expression was up-regulated in the livers of CCl4-treated mice [64]. The expression levels of HOTAIR were also increased in cirrhotic liver tissues from HBV patients and colocalized with ACTA2, indicating that HSCs may be the primary source for HOTAIR in fibrotic liver [36]. A functional characterization of the lncRNA demonstrated that the overexpression of HOTAIR induced cell proliferation and elevated levels of ACTA2 and COL1A1, as well as fibrosis-related genes, such as matrix metalloproteinase 2 (MMP2) and MMP9 [64].…”

“…The silencing of PVT1 in primary HSCs not only reduced the cell proliferation, but also decreased the protein levels of Actα2 and Col1α1 [36]. The PVT1 knockdown in primary HSCs was also associated with changes in the markers of the EMT process, indicating a possible mechanism by which this lncRNA promotes hepatic fibrosis [127].…”

“…NEAT1 overexpression promoted the activation of HSCs and increased levels of Actα2 and Col1α1, indicating that this lncRNA plays a role in HSC activation [36]. NEAT1 overexpression corresponded with decreased levels of miR-122, which was identified to regulate NEAT1 effects on the activation of HSCs by a mechanism associated with Kruppel-like factor 6 (Klf6) [36,74]. The expression of NEAT1 was up-regulated in HCC, while its knockdown was correlated with decreases not only in HCC cell proliferation, but with also invasion, and migration via regulating heterogeneous nuclear ribonucleoprotein A2 (hnRNP A2) [75].…”

“…LncRNAs found in animal models were also highly expressed in fibrosis-related NAFLD, including NEAT1, MALAT1, and PVT1. Another study suggested that some lncRNAs identified in a CCl4 mouse model, namely, APTR, MALAT1, NEAT1, and HOTAIR, may also be related to NAFLD fibrosis in humans [36].…”

“…The expression of NEAT1 was found to be increased in primary HSCs derived from CCl4-treated mice compared to control mice [74]. NEAT1 overexpression promoted the activation of HSCs and increased levels of Actα2 and Col1α1, indicating that this lncRNA plays a role in HSC activation [36]. NEAT1 overexpression corresponded with decreased levels of miR-122, which was identified to regulate NEAT1 effects on the activation of HSCs by a mechanism associated with Kruppel-like factor 6 (Klf6) [36,74].…”