Osteopontin acts as a negative regulator of autophagy accelerating lipid accumulation during the development of nonalcoholic fatty liver disease

Abstract

2020) Osteopontin acts as a negative regulator of autophagy accelerating lipid accumulation during the development of nonalcoholic fatty liver disease, Artificial Cells, Nanomedicine, and Biotechnology, 48:1, 159-168, ABSTRACT Accumulating evidence links osteopontin (OPN), a pro-fibrogenic extracellular matrix protein, to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). In this study, liver tissues isolated from nonalcoholic steatohepatitis (NASH) patients expressed higher OPN than those of controls. However, the exact mechanism(s) for this phenomenon is yet to be clarified. Autophagy is the natural, regulated degradation and recycling of a cell's dysfunctional components, in order to maintain homeostasis. Increasing evidence supports that autophagy can constitute an effective Defence mechanism against NAFLD conditions. Herein, we constructed NAFLD mice model by high-fat (HF) and methionine-choline-deficient (MCD) diet and found that OPN is upregulated in livers of NAFLD mice. Besides, secreted OPN inhibited autophagosome-lysosome fusion via binding with its receptors integrin aVb3 and aVb5 in HepG2 cells supplemented with free fatty acids (FFA) and the livers of NAFLD mice. Silencing of OPN attenuated autophagy impairment and reduced lipid accumulation, while supplementation of OPN exhibited the opposite effect. Furthermore, treatment with anti-OPN Ab significantly attenuated steatosis as well as autophagy impairment in the liver. Our findings indicated that OPN plays a vital role in the pathogenesis of the development of NAFLD via autophagy impairment, which might represent a potential new therapeutic target for the treatment of NAFLD. ARTICLE HISTORY

Autophagy in Hepatic Steatosis: A Structured Review

“…The same group described impaired autophagolysosome formation and acidification, mediated by upregulation of the C-X-C motif chemokine 10, using HFHC and MCD as steatosis models (Zhang et al, 2017). Similarly, Tang et al (2020) promoted steatosis using HFD, the MCD diet, and cell models, and found decreased autophagic flux due to deficient autophagolysosome formation, which the authors ascribe to increased synthesis of osteopontin (OPN). The neutralization of OPN restored autophagic flux and reduced triglyceride accumulation.…”

Osteopontin Takes Center Stage in Chronic Liver Disease

“…(35) Moreover, Opn −/− mice fed the methionine cholinedeficient diet or an HFD with 2% cholesterol show no effect on liver steatosis, but protection from fibrosis. (36) OPN plays a role in the progression of nonalcoholic steatohepatitis (NASH) by inhibiting autophagy (37) and increasing hepatocyte senescence. (38) Data from patients and mice with NASH reveal that OPN is up-regulated in hepatocytes and infiltrated MFs (unpublished observations).…”

The interplay of microRNAs and transcription factors in autophagy regulation in nonalcoholic fatty liver disease

“…Rubicon is posttranscriptionally upregulated in HepG2 cells treated with saturated fatty acids and in the liver of HFD-fed mice 54 . In a recent chemokine study, osteopontin, a chemokine-like phosphorylated glycoprotein, promoted NAFLD progression by impairing autophagy 57 . Osteopontin secreted from fatty liver inhibits autophagosome–lysosome fusion by binding the integrins αVβ3 and αVβ5, and autophagic flux is recovered when αVβ3 and αVβ5 are blocked using specific antibodies.…”