ReviewNASH and atherosclerosis are two aspects of a shared disease: Central role for macrophages
Introduction
The term ‘non-alcoholic fatty liver disease’ (NAFLD) is used to describe a variety of liver diseases of different severity, from pure steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis and, rarely, hepatocellular carcinoma [1]. NASH is viewed as the hepatic event of the metabolic syndrome and it is characterized by hepatic triglyceride (TG) accumulation (i.e. steatosis), in combination with hepatic inflammation. In general, the distinction between NASH and NAFLD is difficult to make in human studies, since a liver biopsy is the only golden standard to distinguish simple steatosis from NASH. The importance of NAFLD and its strong relationship with the metabolic syndrome has stimulated interest in the possible role of the liver in the development of cardiovascular diseases (CVD). Indeed, NAFLD patients have a higher risk of death than the general population, mainly due to CVD or liver-related causes [2]. However, the close interrelationships between fatty liver diseases, the metabolic syndrome and atherosclerosis make it extremely difficult to dissect the cause–effect relationship leading to increased CVD risk.
Atherosclerosis is characterized by the thickening and hardening of the arteries and is a main cause of myocardial infarction or stroke, which is the most common reason of death in the Western world [3]. Monocyte recruitment and macrophage maturation accompanied by uptake of modified LDLs via scavenger receptors (e.g. scavenger receptor A and CD36) gives rise to foam cells in the atheroma and is a key event in the formation of the earliest vascular lesions [4]. At later stages of the disease, growth factor released by macrophages in the plaque cause proliferation of smooth muscle cells and the plaque becomes fibrotic. Ruptured plaques usually have a fibrous cap heavily infiltrated by macrophages. These macrophages are activated at the site of plaque disruption and are capable of degrading extracellular matrix by phagocytosis or by stimulating production of metalloproteases, which weaken the fibrous cap and predispose the plaque to rupture [5]. Spontaneous plaque rupture or acute interventions expose active tissue factor, which is found in abundance in atherosclerotic plaques, in the core to circulating blood, triggering thrombosis [6]. These atherogenic processes are thought to be triggered by well identified risk factors, such as hypertension, hyperlipidemia, diabetes mellitus, and cigarette smoking [7]. Unlike atherosclerosis, which has a complex multifactor etiology, the etiology of NASH was until recently viewed as a paradigm of “two-hit” model [8]. According to this model, hepatic steatosis is the critical first hit, thereby sensitizing the liver to further insults, leading to hepatic inflammation and further liver damage. Thus, unlike atherosclerosis that is driven by inflammation besides lipid accumulation, the inflammatory response in NASH was considered to be a consequence rather than a cause of the disease according to the two-hit hypothesis [8]. Among the well known examples of lipotoxic cellular injuries that can trigger hepatocytes death and inflammation during NASH is increased fatty acid (FA) oxidation and oxidative stress, alteration of cellular membrane FA and phospholipid composition, alteration of cellular cholesterol content, disturbances in ceramide signaling and direct free FA toxicity [9]. However, while steatosis can lead to inflammation, not every patient with steatosis will further progress into NASH. Therefore, it is thought that the accumulation of excessive TG and the development of hepatic injury occur in parallel but independently. Moreover, recent reports in animal models have raised doubts about steatosis and apoptosis as a necessary precondition for the development of hepatic inflammation, as inflammation can develop very early after a short period of high fat feeding and can develop alongside to steatosis [10], [11]. Instead, an increasing number of studies emphasize the central role of activated macrophages in the early development of NASH and thus proposing a pathophysiological mechanism similar to atherosclerosis. Based on this evidence, we believe that NASH is not merely an early mediator of atherosclerosis but actually another aspect of the same disease.
In this review, we will summarize the current knowledge on the similarity in epidemiology, pathophysiology, diagnosis and therapy of both NASH and atherosclerosis. Based on these similarities, we put forward the hypothesis that NASH and atherosclerosis are actually two aspects of a shared disease, with a common etiology involving the local presence of activated macrophages. In addition, the clinical applications of these similarities will be discussed.
Section snippets
NASH as a risk factor for CVD
Many observations support an association between NAFLD and increased risk of developing CVD. However, since it is relatively difficult to obtain liver biopsies, these studies do not differentiate between simple steatosis and NASH. Thus, very few studies have investigated the direct correlation between hepatic inflammation and atherosclerosis. In addition, although the liver has a critical role in inducing, sustaining and further exacerbating systemic inflammation, it is difficult to estimate
Central role for inflammation in the etiology of CVD and NASH
Macrophages play an essential role during the disease process of atherosclerosis by communicating inflammatory signals among metabolic tissues in response to overnutrition and insulin resistance and by scavenging modified lipids. Macrophages can accumulate large amounts of lipids, transform into foam cells and drive atherogenesis [51], [52], [53], [54]. The same process of accumulation of lipid-loaded macrophages was observed in NASH, where hyperlipidemic mice demonstrated bloated foamy Kupffer
Therapy
The lack of adequately powered randomized controlled trials of sufficient duration and with histological end-points, as well as the lack of a suitable animal model that faithfully recapitulates the pathophysiology of human NASH, are major obstacles in developing therapy for NASH. Thus, a rational treatment for NASH patients is currently absent. Based on the ‘two hit’ model, in which steatosis precedes inflammation, the main focus for therapy is currently aimed at steatosis. However, since
Concluding remarks – NASH and atherosclerosis are two aspects of a shared disease
The association between fatty liver diseases and CVD risk was formulated many years ago. So far, most of the studies did not separate between NAFLD and NASH and therefore did not address the fundamental role of macrophages in both of these diseases. Fortunately, the past few years have brought remarkable advances in our understanding of the pathogenesis NASH, often by the extension of research in the atherosclerosis field. A plethora of these studies indicate that NASH further exacerbates CVD
Acknowledgements
R. Shiri-Sverdlov: Veni: 916.76.070 (2006/00496/MW); Maag Lever Darm Stichting (MLDS) (WO 08-16 + WO 10-65); P.C.N. Rensen: Established Investigator of the Netherlands Heart Foundation (NHS 2009.T038); CTMM, Atherosclerosis NASH.
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