Fat: a matter of disturbance for the immune system

Abstract

Obesity is increasingly being recognized as a risk factor for a number of benign and malignant gastrointestinal conditions. However, literature on the underlying pathophysiological mechanisms is sparse and ambiguous. There is compelling evidence that both overnutrition and undernutrition negatively interfere with the immune system. Overnutrition has been found to increase susceptibility to the development of inflammatory diseases, autoimmune diseases and cancer. In the regulation of immune and inflammatory processes, white adipose tissue plays a critical role, not only as an energy store but also as an important endocrine organ. The obese state is characterised by a low-grade systemic inflammation, mainly as a result of increased adipocytes as well as fat resident- and recruited-macrophage activity. In the past few years, various products of adipose tissue including adipokines and cytokines have been characterised and a number of pathways linking adipose tissue metabolism with the immune system have been identified. Activation of the innate immune system plays a major role in hepatic steatosis. Non-alcoholic fatty liver disease includes a wide spectrum of diseases, from pure steatosis to non-alcoholic steatohepatitis in the absence of significant alcohol consumption. Although steatosis is considered a non-progressive disease, non-alcoholic steatohepatitis may deteriorate in advanced chronic liver diseases, cirrhosis, and hepatocellular carcinoma. An important parallel between obesity-related pathology of adipose tissue and liver pertains to the emerging role of macrophages, and growing evidence suggests that Kupffer cells critically contribute to progression of non-alcoholic fatty liver disease. Moreover, a close link between specific immune activation and atherosclerosis has been well established, suggesting that fat can directly trigger immune responses. This review discusses the role of fat as "a matter of disturbance for the immune system" with a focus on hepatic steatosis.

Figure 1

Effects of adipocytokines on regulation of the immune response. IL: Interleukin; IFN: Interferon; MCP: Monocyte chemotactic protein; NK: Natural Killer; TNF-α: Tumor necrosis factor α; NFκB: Nuclear factor κB.

Figure 2

Simplified scheme of Natural Killer/Natural Killer T cell role in liver diseases. Natural Killer (NK) interacts with major and minor histocompatibility antigens expressed on several liver cells and kill and/or produce cytokines having several effects on the tissue. More complex is the role of NKT cells. These cells specifically recognize an antigen expressed in the context of a CD1 molecule and, upon recognition through an invariant TCR, secrete a large amount of cytokines having pleiotropic, sometimes controversial effects, whose overall results are due to the cytokine milieu and to the conditioning of the functions of other immune cells. This scenario is further complicated by the fact that many soluble factors (for instance cytokines) and hedgehog ligands may activate NK or NKT. IL: Interleukin; TNF-α: Tumor necrosis factor α; HCC: Hepatocellular carcinoma; HSCs: Hepatic stellate cells; GM-CSF: Granulocyte-macrophage colony stimulating factor; APC: Antigen presenting cell.

Figure 3

Effects of the activation of Kupffer cells in non-alcoholic fatty liver disease. NAFLD: Non-alcoholic fatty liver disease; NKT: Natural Killer T cells; ROS: Reactive oxygen species.

Figure 4

Complex network of soluble mediators derived from immune cells and adipocytes. MCP: Monocyte chemotactic protein; TNF-α: Tumor necrosis factor α; IL: Interleukin.