LncRNA-H19 promotes hepatic lipogenesis by directly regulating miR-130a/PPARγ axis in non-alcoholic fatty liver disease

Abstract

Background: As one of the most common liver disorders worldwide, non-alcoholic fatty liver disease (NAFLD) begins with the abnormal accumulation of triglyceride (TG) in the liver. Long non-coding RNA-H19 was reported to modulate hepatic metabolic homeostasis in NAFLD. However, its molecular mechanism of NAFLD was not fully clear. Methods: In vitro and in vivo models of NAFLD were established by free fatty acid (FFA) treatment of hepatocytes and high-fat feeding mice, respectively. Hematoxylin and Eosin (H&E) and Oil-Red O staining detected liver tissue morphology and lipid accumulation. Immunohistochemistry (IHC) staining examined peroxisome proliferator-activated receptor γ (PPARγ) level in liver tissues. ELISA assay assessed TG secretion. Luciferase assay and RNA pull down were used to validate regulatory mechanism among H19, miR-130a and PPARγ. The gene expression in hepatocytes and liver tissues was detected by quantitative real-time PCR (qRT-PCR) and Western blotting. Results: H19 and PPARγ were up-regulated, while miR-130a was down-regulated in NAFLD mouse and cellular model. H&E and Oil-Red O staining indicated an increased lipid accumulation. Knockdown of H19 inhibited steatosis and TG secretion in FFA-induced hepatocytes. H19 could bind to miR-130a, and miR-130a could directly inhibit PPARγ expression. Meanwhile, miR-130a inhibited lipid accumulation by down-regulating NAFLD-related genes PPARγ, SREBP1, SCD1, ACC1 and FASN. Overexpression of miR-130a and PPARγ antagonist GW9662 inhibited lipogenesis and TG secretion, and PPARγ agonist GW1929 reversed this change induced by miR-130a up-regulation. Conclusion: Knockdown of H19 alleviated hepatic lipogenesis via directly regulating miR-130a/PPARγ axis, which is a novel mechanistic role of H19 in the regulation of NAFLD.

Long non‐coding RNA (lncRNA) H19 induces hepatic steatosis through activating MLXIPL and mTORC1 networks in hepatocytes

“…C, Paraffin sections were further subjected to IHC staining with antibodies against mTOR, p-mTOR, LIPIN1, SREBP and MLXIPL. 56 Moreover, a recent study suggests that H19 may serve as a lipid sensor by synergizing with the RNA-binding polypyrimidine tract-binding protein 1 (PTBP1) to modulate hepatic metabolic homeostasis because deletion of H19 or knockdown of PTBP1 abolished high-fat and high-sucrose diet-induced steatosis. Representative images are shown while representative positive stains are indicated by arrows.…”

“…55 Consistent with our findings, H19 was shown to promote hepatic lipogenesis by regulating miR-130a/PPARγ axis in NAFLD animal model. 56 Moreover, a recent study suggests that H19 may serve as a lipid sensor by synergizing with the RNA-binding polypyrimidine tract-binding protein 1 (PTBP1) to modulate hepatic metabolic homeostasis because deletion of H19 or knockdown of PTBP1 abolished high-fat and high-sucrose diet-induced steatosis. 57 Nonetheless, it is conceivable that H19 may regulate hepatic lipid homeostasis through diverse mechanisms, especially implicating the PI3K/AKT/mTOR signalling axis.…”

Non-Coding RNAs as Potential Novel Biomarkers for Early Diagnosis of Hepatic Insulin Resistance

“…These conflicting findings may possibly be explained by the fact that each study was based on a different in vivo model. Liu et al [43] observed H19 up-regulation, Srebp-1c, Acc1, Scd1, Fasn and Pparγ, increased expression in a model of NAFLD. This study was also conducted based on HFD mice model, so it is possible that H19 expression varies between different models, especially since lncRNA expression patterns are tissue-and state-specific.…”

Long non-coding RNAs in liver diseases: Focusing on nonalcoholic fatty liver disease, alcohol-related liver disease, and cholestatic liver disease

“…H19 as well as genes that are involved in hepatic lipogenesis are upregulated in mice fed with high fat diet. 39,40 H19 directly downregulates the expression of miR-130a which in turn inhibits the expression of peroxisome proliferator-activated receptor γ level in the liver. 39 It also promotes steatosis by regulating transcription factor MLX-interacting protein-like (MLXIPL) or carbohydrateresponsive element-binding protein.…”

“…39,40 H19 directly downregulates the expression of miR-130a which in turn inhibits the expression of peroxisome proliferator-activated receptor γ level in the liver. 39 It also promotes steatosis by regulating transcription factor MLX-interacting protein-like (MLXIPL) or carbohydrateresponsive element-binding protein. 40 H19 also serves as a lipid sensor by synergizing with RNA-binding protein, polypyrimidine tract-binding protein 1 (PTBP1), to modulate hepatic metabolic homeostasis.…”