ArticleBiochimica et biophysica acta2016
Osteopontin is a proximal effector of leptin-mediated non-alcoholic steatohepatitis (NASH) fibrosis.
Article in Biochimica et biophysica acta, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 52 citations in OpenAlex.
- Canonical and Non-Canonical Regulators of Lipid Metabolism in the Liver and the "Liver-Other Organs" Axes.International journal of molecular sciences · 2026Review
- Label-Free Urinary Proteomics Uncovers Immune-Related Non-Invasive Biomarkers for Primary Biliary Cholangitis.International journal of molecular sciences · 2026Article
- Immunometabolic Organ Crosstalk in Heart Failure with Preserved Ejection Fraction: The Role of Dietary Patterns in Obesity-Related Inflammation.Nutrients · 2026Review
- Mechanisms and therapeutic insights into MASH-associated fibrosis.Trends in endocrinology and metabolism: TEM · 2026Review
- Metabolic dysfunction-associated steatotic liver disease and steatohepatitis-associated hepatocarcinoma preclinical models.Nature reviews. Gastroenterology & hepatology · 2026Review
- Osteopontin Promotes Cholangiocyte Secretion of Chemokines to Support Macrophage Recruitment and Fibrosis in MASH.Liver international : official journal of the International Association for the Study of the Liver · 2025Article
- Review
- Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): the interplay of gut microbiome, insulin resistance, and diabetes.Frontiers in medicine · 2025Review
- Osteokines in Nonalcoholic Fatty Liver Disease.Current obesity reports · 2024Review
- Analysis of culture and RNA isolation methods for precision-cut liver slices from cirrhotic rats.Scientific reports · 2024Article
- Melanocortin-4 receptor in macrophages attenuated angiotensin II-induced abdominal aortic aneurysm in mice.Scientific reports · 2023Article
- Article
- Decoding liver fibrogenesis with single-cell technologies.Life medicine · 2022Review
- Inflammatory-driven NK cell maturation and its impact on pathology.Frontiers in immunology · 2022Review
- Review
- Pathophysiologic importance of visceral adipose tissue in women with heart failure and preserved ejection fraction.European heart journal · 2021Article
- Non-alcoholic fatty liver disease and heart failure with preserved ejection fraction: from pathophysiology to practical issues.ESC heart failure · 2021Review
- Inflammatory Mechanisms Underlying Nonalcoholic Steatohepatitis and the Transition to Hepatocellular Carcinoma.Cancers · 2021Review
- Serum osteopontin can improve papillary thyroid cancer risk assessment of Bethesda III thyroid nodules: a preliminary study.Endocrine oncology (Bristol, England) · 2021Article
- Quantitative Expression of Key Cancer Markers in the AS-30D Hepatocarcinoma Model.Frontiers in oncology · 2021Article
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Authors and funding
23 authors at 9 institutions in 5 countries.
Funding
Abstract
introductionLiver fibrosis develops when hepatic stellate cells (HSC) are activated into collagen-producing myofibroblasts. In non-alcoholic steatohepatitis (NASH), the adipokine leptin is upregulated, and promotes liver fibrosis by directly activating HSC via the hedgehog pathway. We reported that hedgehog-regulated osteopontin (OPN) plays a key role in promoting liver fibrosis. Herein, we evaluated if OPN mediates leptin-profibrogenic effects in NASH.
methodsLeptin-deficient (ob/ob) and wild-type (WT) mice were fed control or methionine-choline deficient (MCD) diet. Liver tissues were assessed by Sirius-red, OPN and αSMA IHC, and qRT-PCR for fibrogenic genes. In vitro, HSC with stable OPN (or control) knockdown were treated with recombinant (r)leptin and OPN-neutralizing or sham-aptamers. HSC response to OPN loss was assessed by wound healing assay. OPN-aptamers were also added to precision-cut liver slices (PCLS), and administered to MCD-fed WT (leptin-intact) mice to determine if OPN neutralization abrogated fibrogenesis.
resultsMCD-fed WT mice developed NASH-fibrosis, upregulated OPN, and accumulated αSMA+ cells. Conversely, MCD-fed ob/ob mice developed less fibrosis and accumulated fewer αSMA+ and OPN+ cells. In vitro, leptin-treated HSC upregulated OPN, αSMA, collagen 1α1 and TGFβ mRNA by nearly 3-fold, but this effect was blunted by OPN loss. Inhibition of PI3K and transduction of dominant negative-Akt abrogated leptin-mediated OPN induction, while constitutive active-Akt upregulated OPN. Finally, OPN neutralization reduced leptin-mediated fibrogenesis in both PCLS and MCD-fed mice.
conclusionOPN overexpression in NASH enhances leptin-mediated fibrogenesis via PI3K/Akt. OPN neutralization significantly reduces NASH fibrosis, reinforcing the potential utility of targeting OPN in the treatment of patients with advanced NASH.
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