C-C Chemokine Receptor 2 (CCR2) Regulates the Hepatic Recruitment of Myeloid Cells That Promote Obesity-Induced Hepatic Steatosis

Department of Medicine, Columbia University, New York, New York, USA.
Diabetes (Impact Factor: 8.1). 04/2010; 59(4):916-25. DOI: 10.2337/db09-1403
Source: PubMed


Obesity induces a program of systemic inflammation that is implicated in the development of many of its clinical sequelae. Hepatic inflammation is a feature of obesity-induced liver disease, and our previous studies demonstrated reduced hepatic steatosis in obese mice deficient in the C-C chemokine receptor 2 (CCR2) that regulates myeloid cell recruitment. This suggests that a myeloid cell population is recruited to the liver in obesity and contributes to nonalcoholic fatty liver disease.
We used fluorescence-activated cell sorting to measure hepatic leukocyte populations in genetic and diet forms of murine obesity. We characterized in vivo models that increase and decrease an obesity-regulated CCR2-expressing population of hepatic leukocytes. Finally, using an in vitro co-culture system, we measured the ability of these cells to modulate a hepatocyte program of lipid metabolism.
We demonstrate that obesity activates hepatocyte expression of C-C chemokine ligand 2 (CCL2/MCP-1) leading to hepatic recruitment of CCR2(+) myeloid cells that promote hepatosteatosis. The quantity of these cells correlates with body mass and in obese mice represents the second largest immune cell population in the liver. Hepatic expression of CCL2 increases their recruitment and in the presence of dietary fat induces hepatosteatosis. These cells activate hepatic transcription of genes responsible for fatty acid esterification and steatosis.
Obesity induces hepatic recruitment of a myeloid cell population that promotes hepatocyte lipid storage. These findings demonstrate that recruitment of myeloid cells to metabolic tissues is a common feature of obesity, not limited to adipose tissue.

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Available from: Anthony Ferrante, Dec 22, 2015
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    • "Ccr2 is expressed on monocytes and macrophages, where it serves as a crucial recruitment factor by directing cells to sites of injury and inflammation[4]. Ccr2 is one of the M1 macrophage phenotype markers5678and has been shown to be involved in macrophage-dependent inflammatory responses in various chronic inflammatory diseases, including atherosclerosis, Alzheimer disease, uveitis, and choroidal neovascularization9101112Ccr2 is expressed at the cell surface both variably and under stringent regulation[13]; however, the underlying mechanisms are obscure. AMP-activated protein kinase (AMPK) is a serine/threonine kinase that regulates energy homeostasis and metabolic stress[14]. "
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    ABSTRACT: C-C chemokine receptor 2 (Ccr2) is a key pro-inflammatory marker of classic (M1) macrophage activation. Although Ccr2 is known to be expressed both constitutively and inductively, the full regulatory mechanism of its expression remains unclear. AMP-activated protein kinase (AMPK) is not only a master regulator of energy homeostasis but also a central regulator of inflammation. In this study, we sought to assess AMPK's role in regulating RAW264.7 macrophage Ccr2 protein levels in resting (M0) or LPS-induced M1 states. In both M0 and M1 RAW264.7 macrophages, knockdown of the AMPKα1 subunit by siRNA led to increased Ccr2 levels whereas pharmacologic (A769662) activation of AMPK, attenuated LPS-induced increases in Ccr2 expression in an AMPK dependent fashion. The increases in Ccr2 levels by AMPK downregulation were partially reversed by NF-κB inhibition whereas TNF-a inhibition had minimal effects. Our results indicate that AMPK is a negative regulator of Ccr2 expression in RAW264.7 macrophages, and that the mechanism of action of AMPK inhibition of Ccr2 is mediated, in part, through the NF-κB pathway.
    Full-text · Article · Jan 2016 · PLoS ONE
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    • "Indeed, the recruitment of inflammatory cells is involved in the resolution of inflammation. However, the persistent presence of these cells causes, at long term, cellular injury [9] [10]. Although steatosis is described as a result of nutrient overload, the time required for fat accumulation in the liver and inflammation arising from the consumption of a carbohydraterich diet has not been well elucidated. "
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    ABSTRACT: Hepatic diseases are comorbidities caused by obesity and are influenced by diet composition. The aim of this study was to evaluate the kinetics of metabolic and inflammatory liver dysfunction induced by a high-refined carbohydrate-containing (HC) diet and to determine how platelet-activating factor (PAF) modulates the liver lipid content of mice. BALB/c mice were fed a chow or HC diet for the following experimental periods: 1 and 3 days, 1, 2, 4, 6, 8, 10 and 12 weeks. Wild-type (WT) and PAF receptor-deficient (PAFR(-/-)) mice were fed the same diets for 8 weeks. Mice fed with HC diet showed higher triglycerides and cholesterol levels, fibrosis and inflammation in the liver. The number of neutrophils migrating into the liver was also increased in mice fed with HC diet. However, transaminase levels did not change. PAFR(-/-) mice fed with HC diet showed more steatosis, oxidative stress and higher transaminases levels associated with lower inflammation than WT mice. The consumption of HC diet altered the metabolic and inflammatory response in the liver and was worse in PAFR(-/-) mice. We suggest that PAF regulates liver lipid content and dyslipidemia, protecting the mice from lipotoxicity and liver damage. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · May 2015 · The Journal of Nutritional Biochemistry
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    • "Lipoapoptosis is a histologic hallmark of nonalcoholic steatohepatitis (NASH) and correlates with disease severity[11]. More importantly, the liver contains abundant resident macrophages, Kupffer cells, and their activation or an influx of recruited macrophages has been implicated in the progression of NASH-associated liver injury.[25] Of note, cell death by apoptosis has recently been associated with release of cytokines including monocyte chemotactic protein 1 (MCP-1) which could provide a signal for monocyte recruitment into the liver[8]. "
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    ABSTRACT: Low-grade chronic inflammation is a cardinal feature of the metabolic syndrome, yet its pathogenesis is not well defined. The purpose of this study was to examine the role of TRAIL receptor (TR) signaling in the pathogenesis of obesity-associated inflammation utilizing mice with the genetic deletion of TR. TR knockout (TR(-/-)) mice and their littermate wild-type (WT) mice were fed a diet high in saturated fat, cholesterol and fructose (FFC) or chow. Metabolic phenotyping, liver injury, and liver and adipose tissue inflammation were assessed. Chemotaxis and activation of mouse bone marrow-derived macrophages (BMDMϕ) was measured. Genetic deletion of TR completely repressed weight gain, adiposity and insulin resistance in FFC-fed mice. Moreover, TR(-/-) mice suppressed steatohepatitis, with essentially normal serum ALT, hepatocyte apoptosis and liver triglyceride accumulation. Gene array data implicated inhibition of macrophage-associated hepatic inflammation in the absence of the TR. In keeping with this, there was diminished accumulation and activation of inflammatory macrophages in liver and adipose tissue. TR(-/-) BMDMφ manifest reduced chemotaxis and diminished activation of nuclear factor-κ B signaling upon activation by palmitate and lipopolysaccharide. These data advance the concept that macrophage-associated hepatic and adipose tissue inflammation of nutrient excess requires TR signaling. Copyright © 2014. Published by Elsevier B.V.
    Full-text · Article · Nov 2014 · Journal of Hepatology
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