Elevated Expression of Osteopontin May Be Related to Adipose Tissue Macrophage Accumulation and Liver Steatosis in Morbid Obesity

Institut National de la Santé et de la Recherche Médicale, U895, Team 8, Hepatic Complications in Obesity, Nice, France.
Diabetes (Impact Factor: 8.1). 11/2008; 58(1):125-33. DOI: 10.2337/db08-0400
Source: PubMed

ABSTRACT Osteopontin (OPN) plays an important role in the development of insulin resistance and liver complications in dietary murine models. We aimed to determine the expression pattern of OPN and its receptor CD44 in obese patients and mice according to insulin resistance and liver steatosis.
OPN and CD44 expressions were studied in 52 morbidly obese patients and in mice. Cellular studies were performed in HepG2 cells.
Hepatic OPN and CD44 expressions were strongly correlated with liver steatosis and insulin resistance in obese patients and mice. This increased OPN expression could be due to the accumulation of triglycerides, since fat loading in HepG2 promotes OPN expression. In contrast, OPN expression in adipose tissue (AT) was enhanced independently of insulin resistance and hepatic steatosis in obese patients. The elevated OPN expression in AT was paralleled with the AT macrophage infiltration, and both phenomena were reversed after weight loss. The circulating OPN level was slightly elevated in obese patients and was not related to liver steatosis. Further, AT did not appear to secrete OPN. In contrast, bariatric surgery-induced weight loss induced a strong increase in circulating OPN.
The modestly elevated circulating OPN levels in morbidly obese patients were not related to liver steatosis and did not appear to result from adipose tissue secretion. In subcutaneous AT, expression of OPN was directly related to macrophage accumulation independently from liver complications. In contrast, hepatic OPN and CD44 expressions were related to insulin resistance and steatosis, suggesting their local implication in the progression of liver injury.

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Available from: Jean Gugenheim, Sep 28, 2015
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    • "Obesity and type 2 diabetes are strongly associated with a spectrum of hepatic disorders collectively referred to as non-alcoholic fatty liver disease (NAFLD). NAFLD spans a spectrum from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH) and steatofibrosis ultimately leading to liver cirrhosis and hepatocellular carcinoma [97]. Notably, OPN expression is also markedly upregulated in the liver in obesity, and hepatic OPN levels correlate with liver triacylglycerol levels [97,102]. "
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    ABSTRACT: Since its first description more than 20 years ago osteopontin has emerged as an active player in many physiological and pathological processes, including biomineralization, tissue remodeling and inflammation. As an extracellular matrix protein and proinflammatory cytokine osteopontin is thought to facilitate the recruitment of monocytes/macrophages and to mediate cytokine secretion in leukocytes. Modulation of immune cell response by osteopontin has been associated with various inflammatory diseases and may play a pivotal role in the development of adipose tissue inflammation and insulin resistance. Here we summarize recent findings on the role of osteopontin in metabolic disorders, particularly focusing on diabetes and obesity.
    Molecular Metabolism 07/2014; 3(4). DOI:10.1016/j.molmet.2014.03.004
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    • "The adipose tissue expansion that takes place in obesity is associated with macrophage accumulation [10]. OPN represents a potent chemoattractant and activator for macrophages [44]. "
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    ABSTRACT: Osteopontin (OPN) is a multifunctional extracellular matrix (ECM) protein involved in multiple physiological processes. OPN expression is dramatically increased in visceral adipose tissue in obesity and the lack of OPN protects against the development of insulin resistance and inflammation in mice. We sought to unravel the potential mechanisms involved in the beneficial effects of the absence of OPN. We analyzed the effect of the lack of OPN in the development of obesity and hepatic steatosis induced by a high-fat diet (HFD) using OPN-KO mice. OPN expression was upregulated in epididymal white adipose tissue (EWAT) and liver in wild type (WT) mice with HFD. OPN-KO mice had higher insulin sensitivity, lower body weight and fat mass with reduced adipose tissue ECM remodeling and reduced adipocyte size than WT mice under a HFD. Reduced MMP2 and MMP9 activity was involved in the decreased ECM remodeling. Crown-like structure number in EWAT as well as F4/80-positive cells and Emr1 expression in EWAT and liver increased with HFD, while OPN-deficiency blunted the increase. Moreover, our data show for the first time that OPN-KO under a HFD mice display reduced fibrosis in adipose tissue and liver, as well as reduced oxidative stress in adipose tissue. Gene expression of collagens Col1a1, Col6a1 and Col6a3 in EWAT and liver, as well as the profibrotic cytokine Tgfb1 in EWAT were increased with HFD, while OPN-deficiency prevented this increase. OPN deficiency prevented hepatic steatosis via reduction in the expression of molecules involved in the onset of fat accumulation such as Pparg, Srebf1, Fasn, Mogat1, Dgat2 and Cidec. Furthermore, OPN-KO mice exhibited higher body temperature and improved BAT function. The present data reveal novel mechanisms of OPN in the development of obesity, pointing out the inhibition of OPN as a promising target for the treatment of obesity and fatty liver.
    PLoS ONE 05/2014; 9(5):e98398. DOI:10.1371/journal.pone.0098398 · 3.23 Impact Factor
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    • "Our data reveal the independent and overlapping roles of CCR2 and CD44 in development and progression of hepatic inflammation during fatty liver disease. Our findings reinforce studies in humans that have identified CCR2 and CD44 as being increased in NASH patients and they establish a possible link between these two molecules in lipid mediated hepatitis progression in so far as Ccr2−/− mice are largely protected from CD44 mediated HA binding [6], [7], [20]. The monocytes emerging in the liver during hepatitis progression bare the hallmarks of inflammatory monocytes as they display a CCR2+, Gr-1+ (Ly6G), iNOS+ phenotype. "
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    ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is a common disease with a spectrum of presentations. The current study utilized a lithogenic diet model of NAFLD. The diet was fed to mice that are either resistant (AKR) or susceptible (BALB/c and C57BL/6) to hepatitis followed by molecular and flow cytometric analysis. Following this, a similar approach was taken in congenic mice with specific mutations in immunological genes. The initial study identified a significant and profound increase in multiple ligands for the chemokine receptor CCR2 and an increase in CD44 expression in susceptible C57BL/6 (B6) but not resistant AKR mice. Ccr2(-/-) mice were completely protected from hepatitis and Cd44(-/-) mice were partially protected. Despite protection from inflammation, both strains displayed similar histological steatosis scores and significant increases in serum liver enzymes. CD45(+)CD44(+) cells bound to hyaluronic acid (HA) in diet fed B6 mice but not Cd44(-/-) or Ccr2(-/-) mice. Ccr2(-/-) mice displayed a diminished HA binding phenotype most notably in monocytes, and CD8(+) T-cells. In conclusion, this study demonstrates that absence of CCR2 completely and CD44 partially reduces hepatic leukocyte recruitment. These data also provide evidence that there are multiple redundant CCR2 ligands produced during hepatic lipid accumulation and describes the induction of a strong HA binding phenotype in response to LD feeding in some subsets of leukocytes from susceptible strains.
    PLoS ONE 06/2013; 8(6):e65247. DOI:10.1371/journal.pone.0065247 · 3.23 Impact Factor
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