Farnesoid X Receptor Protects Hepatocytes From Injury by Repressing miR-199a-3p, Which Increases Levels of LKB1

Abstract

BACKGROUND & AIMS Hepatocyte injury occurs during liver fibrogenesis. MicroRNAs (miRNA) regulate some of these processes, and some are regulated by the farnesoid X receptor (FXR). We investigated the effect of repression of specific miRNAs by FXR in hepatocyte injury using fibrotic liver tissue from patients and hepatocytes. METHODS We used immunohistochemistry or real-time polymerase chain reaction to analyze proteins and miRNAs in human and mouse liver samples. HepG2 cells were transfected with pre-miRNA, antisense oligonucleotides, small interfering RNAs, the 3′-untranslated region of liver kinase B1 (LKB1) (STK11), or constructs for overexpression, and analyzed. RESULTS Liver tissue from patients with severe fibrosis had lower levels of FXR and greater amounts of hepatocyte death than samples from patients with mild disease. Levels of several miRNAs changed when FXR expression was disrupted in the liver; one of these, miR-199a-3p, was significantly up-regulated in patients with severe fibrosis. Activation of FXR by its ligand reduced the level of miR-199a-3p in HepG2 cells. LKB1 messenger RNA was identified as a target of miR-199a-3p, and its expression was reduced in human fibrotic liver tissue. Overexpression of FXR or incubation of cultured hepatocytes with the FXR ligand up-regulated LKB1; LKB1 was not induced in cells transfected with miR-199a-3p. Incubation of HepG2 cells with FXR ligand, or injection of the ligand into mice, protected hepatocytes from injury and increased levels of LKB1; levels of miR-199a-3p were reduced compared with cells that were not incubated with the FXR ligand. Activation of FXR reduced mitochondrial dysfunction and oxidative stress and increased hepatocyte survival. CONCLUSIONS In hepatocytes, FXR represses production of miR-199a-3p. In fibrotic livers of humans and mice, FXR expression is reduced, increasing levels of miR-199a-3p, which reduces levels of LKB1. FXR therefore protects hepatocytes from injury by repressing miR-199a-3p and thereby increasing levels of LKB1.

Plasma microRNA signature as a noninvasive biomarker for acute graft-versus-host disease

“…26 miR-199a-3p was reported to play a role in hepatocyte injury and hepatocellular carcinoma. 25,38 miR-93* regulates cell proliferation, 39 whereas miR30a is associated with autophagy and apoptosis. 40,41 Spearman analysis in our study demonstrated a high correlation between several miRNAs in the panel, suggesting that the above miRNAs have a similar function in the development of aGVHD.…”

“…The 6 altered miRNAs we identified are involved in inflammation, tissue damage, regulation of cell proliferation, and tissue repair, [24][25][26] suggesting increased levels of these miRNAs in the plasma of aGVHD patients may be associated with the immune response and organ damage during aGVHD. We thus evaluated the sensitivity and specificity of these miRNAs in diagnosing aGVHD using ROC analysis.…”

MiR-22-silenced Cyclin A Expression in Colon and Liver Cancer Cells Is Regulated by Bile Acid Receptor

“…FXR KO mice are predisposed to gallstone disease, but activation of FXR ameliorates this condition by restoring the bile acid to cholesterol ratio (16). In humans, FXR expression is markedly reduced in patients with severe cirrhosis and liver cancer (14,15,17). Together, FXR regulatory processes are involved in pathologies ranging from hyperlipidemia to diabetes, from cholestasis to enterohepatic tumors.…”

“…Activation of FXR increases hepatic levels of miR-144, which in turn lowers hepatic ABCA1 and plasma HDL levels (18). FXR protects hepatocytes from injury by repressing miR-199a-3p and thereby increasing levels of LKB1 (17). Activation of FXR also increases the expression of miR-29a in hepatic stellate cells and inhibits extracellular matrix production (19).…”

“…Therefore, FXR plays a vital role in liver and colon cancer development. In human, FXR expression is markedly reduced in patients with severe fibrosis (Ishak score Ͼ 5) and liver can- cer (1,17). The mechanism by which a lack of FXR promotes carcinogenesis has been investigated.…”