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

ABSTRACT 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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    • "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.
    The Journal of Nutritional Biochemistry 05/2015; na(na):na. DOI:10.1016/j.jnutbio.2015.04.004 · 3.79 Impact Factor
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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.
    Journal of Hepatology 11/2014; 62(5). DOI:10.1016/j.jhep.2014.11.033 · 11.34 Impact Factor
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    • "Phagocytosis of neutrophils leads to increased expression of monocyte chemoattractant protein 1 (MCP-1), which is secreted by macrophages, endothelial, Kupffer, and hepatic stellate cells, and determines the recruitment and activation of monocytes and T-lymphocytes (Marra et al. 1998). In fatty liver disease, MCP-1 plays an important role in the transition from simple steatosis to NASH (Haukeland et al. 2006; Obstfeld et al. 2010). While the development of simple fatty liver in response to fasting has been reported in mink (Bjornvad et al. 2004; Mustonen et al. 2005; Rouvinen-Watt et al. 2010), its progression to NASH, i.e., the possible induction of liver inflammation as a result of lipid accumulation, remains to be studied. "
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    ABSTRACT: We investigated the presence of inflammatory signs in the progression of fatty liver disease induced by fasting. Sixty standard black American mink (Neovison vison) were fasted for 0, 1, 3, 5, or 7 days and one group for 7 days followed by re-feeding for 28 days. Liver sections were evaluated histologically and liver mRNA levels indicating endoplasmic reticulum (ER) stress, adipogenic transformation, and inflammation were assessed by quantitative real-time PCR. After 3 days of fasting, the mink had developed moderate liver steatosis. Increased hyaluronan reactivity in lymphocytic foci but no Mallory-Denk bodies were seen in livers of the mink fasted for 5-7 days. Up-regulation of glucose-regulated protein, 78 kDa was observed on day 7 indicating ER stress, especially in the females. Liver lipoprotein lipase and monocyte chemoattractant protein 1 mRNA levels increased in response to 5-7 days of food deprivation, while tumor necrosis factor α (TNF-α) was the highest in the mink fasted for 5 days. The expression of the genes of interest, except for TNF-α, correlated with each other and with the liver fat content. The mRNA levels were found to change more rapidly below n-3/n-6 polyunsaturated fatty acid ratio threshold of 0.15. Following re-feeding, hepatocyte morphology and mRNA abundance returned to pre-fasting levels. Within the studied timeframe, evidence for ER stress, adipogenic transformation, and liver inflammation suggested incipient transition from steatosis to steatohepatitis with potential for development of more severe liver disease. This may present a possibility to influence disease progression before histologically observable steatohepatitis.
    Journal of Comparative Physiology B 07/2014; 184(7). DOI:10.1007/s00360-014-0845-9 · 2.62 Impact Factor
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