Crosstalk between adipose tissue insulin resistance and liver macrophages in non-alcoholic fatty liver disease
Graphical abstract
Introduction
The recent epidemic of chronic liver disease is related to the burden of non-alcoholic fatty liver disease (NAFLD), paralleling the worldwide increase of obesity.1 NAFLD is a complex condition related to metabolic derangements in insulin resistance (IR), but in a subset of patients the liver becomes the target of multiple hits leading to non-alcoholic steatohepatitis (NASH), the histological phenotype that may progressively lead to the development of liver fibrosis, cirrhosis and possibly hepatocellular carcinoma.[1], [2] Understanding the biological and environmental factors that drive the progression to NASH and beyond in some individuals is fundamental to the development of robust methods for diagnosis, risk stratification and therapy.2
The prevailing notion of NASH pathogenesis is that a deranged metabolic milieu specifically interacts with local mediators of hepatic inflammation and fibrosis, but the nature of these interactions has not been fully elucidated.[3], [4] It is generally believed that adipose tissue IR plays a pivotal role in the onset and progression of NAFLD.[5], [6] Briefly, weight gain leads to expansion of adipose tissue and recruitment of macrophages through the secretion of various chemo- and cytokines.7 Inflamed and dysfunctional adipose tissue actively releases free fatty acids (FFAs) into the bloodstream, promotes lipotoxicity in the liver, muscle and pancreas,3 and contributes to systemic inflammation. In the normal liver, resident macrophages or Kupffer cells (KCs) play important regulatory roles through crosstalk with the different cell types and particularly with hepatocytes.8 The pro-inflammatory polarization of hepatic macrophages is considered a hallmark of progressive disease, in the livers of patients with NASH, and an attractive therapeutic target as recently reviewed.8 Hepatic lipid accumulation facilitates pro-inflammatory KC polarization, possibly as a consequence of FFA excess, or signals from surrounding steatotic hepatocytes, such as histidine-rich glycoprotein, extracellular vesicles or damage-associated molecular patterns.8 More recently, data derived from animal models and in vitro studies suggest that both pro-inflammatory KCs and recruited hepatic macrophages (Ly6Chi) contribute to decreased hepatic insulin sensitivity by inhibiting insulin signaling and activating hepatic glucose production.9 However, most data available have been derived from mouse models, which are not fully representative of human NASH, since they reflect certain aspects of the pathogenesis and rarely incorporate the full spectrum of etiology-specific mechanisms.8
Soluble CD163 (sCD163) is the ecto-domain of the hemoglobin-haptoglobin scavenger receptor which is exclusively expressed on macrophages and monocytes. It is shed to the circulation during macrophage activation by metalloprotease activity (e.g. tumor necrosis factor-alpha converting enzyme (TACE/ADAM17)).[10], [11] CD163-positive macrophages are highly expressed in human adipose tissue from obese individuals, while sCD163 levels are associated with hepatic inflammation and fibrosis in patients with NAFLD[12], [13] and decrease after successful life-style intervention and bariatric surgery.[14], [15], [16]
Against this background, we carried out this study to further elucidate the complex interplay between IR in target organs/tissues, macrophage activation and hepatic damage in a well-characterized cohort of non-diabetic patients with biopsy-proven NAFLD.
Section snippets
Study participants
The study was performed in 40 patients with NAFLD, selected from consecutive patients who had a liver biopsy for the evaluation of suspected NAFLD between June 2010 and June 2013 in the Liver Unit of the University of Torino, according to the absence of type 2 diabetes mellitus (T2DM) and morbid obesity (body mass index [BMI] >35); the absence of the 2 latter conditions in our patients unveils the independent contribution of NAFLD to metabolic and inflammatory alterations. Other etiologies of
Characteristics of the study patients
The anthropometric, biochemical, and histological characteristics of the study participants (n = 40) are reported in Table 1. Overall, only one-third of patients (35%) were obese according to BMI, but central obesity was found in more than half (60%) and it was the most common feature of the metabolic syndrome (MetS), followed by hypertension (38%), low HDL-Chol (35%), hyperglycemia (23%) and hypertriglyceridemia (10%). Nevertheless, only 32% of patients met the criteria for the diagnosis of
Discussion
The present study indicates that macrophage activation in the liver of patients with NAFLD, possibly in addition to macrophage activation in the adipose tissue, stems from impaired lipid metabolism in the setting of IR. While the role of adipose tissue inflammation in the onset of IR is not under discussion, it is likely that the overflow of FFAs to the liver is one of the main metabolic sources of activation of resident hepatic macrophages in patients with NAFLD and may be one of the
Financial support
This work was funded by FP7/2007-2013 under grant agreement n.HEALTH-F2-2009-241762, project FLIP and by Horizon 2020 under grant agreement n. 634413, project EPoS for EB and AG. HG received funding from The NOVO Nordisk Foundation, The Danish Strategic Research Council (10-092797) and ‘‘Savværksejer Jeppe Juhl og hustru Ovita Juhls mindelegat’’.
Conflict of interest
The authors declare no conflicts of interest that pertain to this work.
Please refer to the accompanying ICMJE disclosure forms for further details.
Authors’ contributions
CR provided data collection, statistical analysis, interpreted data and drafted the manuscript, KK, RY, SE, MM and MS provided the acquisition of data, interpreted data and critically reviewed the manuscript, CB, MG and FS provided the acquisition of data, HJM, MLA, HV, AG and JG interpreted data and critically reviewed the manuscript, EB and HG led the development of the study concept and design, interpreted data, drafted and finalized the manuscript.
Acknowledgement
Professor Stephen Hamilton-Dutoit, Aarhus University Hospital, is acknowledged for CD163 IHC staining o liver biopsies.
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Prof. Elisabetta Bugianesi and Prof. Henning Grønbæk share co-last authorship.