Review
Insulin resistance, inflammation, and non-alcoholic fatty liver disease

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Non-alcoholic fatty liver disease (NAFLD), the major cause of abnormal liver function in the western world, is often associated with obesity and diabetes. In obese individuals, fat accumulation in the abdominal region affects both lipid and glucose metabolism, and a liver loaded with fat is insulin resistant. Insulin resistance (IR) is often associated with chronic low-grade inflammation, and numerous mediators released from immune cells and adipocytes contribute to development of IR. Recent results showing an important role for these mediators in NAFLD are providing us with a better understanding of this highly prevalent disease with implications for novel therapy development. This review highlights new aspects in development of liver steatosis and the relevance of various cytokines and adipocytokines in NAFLD.

Introduction

Obesity, associated with the development of type 2 diabetes (T2D) and hypertension, also affects liver function 1, 2. In fact, there is now convincing evidence that non-alcoholic fatty liver disease (NAFLD) is a component of the metabolic syndrome [3], and the majority of NAFLD patients are, indeed, overweight or obese. NAFLD is characterized by a broad spectrum of pathologies ranging from simple steatosis and non-alcoholic steatohepatitis (NASH) to liver cirrhosis and hepatocellular carcinoma [4]. Whereas simple steatosis remains a benign process in most affected individuals 5, 6, the presence of liver inflammation (as observed in NASH) is the driving force for the development of fibrosis and cirrhosis [7]. It is estimated that approximately 1–2% of the Western population have NASH [7]. A distinction between simple steatosis and NASH and fibrosis is only possible by liver histology and cannot yet be predicted reliably by clinical or laboratory features 4, 8, 9. Therefore, we not only have to understand why patients develop more advanced stages of this disease but also need to identify noninvasive markers to differentiate NASH from simple steatosis.

Insulin resistance (IR) has been identified as a crucial pathophysiological factor in the development and progression of NAFLD [10]. IR is caused by a variety of factors including genetic determinants, nutrition and lifestyle. It is increasingly recognized that free fatty acids (FFA) and soluble mediators synthesized from immune cells and adipose tissue are crucially involved in regulating insulin action and NAFLD manifestation 11, 12. Adipocytes are known to secrete pro-inflammatory cytokines, including tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6). Because of their historic role in the immune system, these ‘classic’ cytokines are not termed adipocytokines, even though they are also produced by adipocytes. Typical adipocytokines (i.e. those produced almost exclusively by adipose tissue) include mediators such as adiponectin or leptin and are considered major links between obesity, IR and related inflammatory disorders [13].

This review summarizes key aspects in the development of a fatty liver and highlights the role of inflammatory mediators in NAFLD-associated IR. First, insulin signaling and regulation of IR are described because it is increasingly recognized that various inflammatory pathways impair insulin signaling. Another section discusses insights into the development of a fatty liver with the important recent discovery that X-box-binding protein-1 (XBP1) is a key regulator of hepatic lipogenesis. The role of various cytokines and transcription factors involved in inflammatory processes in a fatty liver are then discussed with emphasis on the roles of various adipocytokines such as adiponectin, leptin or resistin in IR and NAFLD.

Section snippets

Insulin signaling and IR

Insulin binds to insulin receptor (insulinR) to activate a cascade of intracellular signaling events [14], including phosphorylation of both its receptor and several members of the insulin receptor substrate (IRS) family (Figure 1). Tyrosine phosphorylation of IRS by insulin is a key event in mediating insulin action and, importantly, is impaired in most cases of IR [15]. Various pathways are activated in response to IRS phosphorylation: the MAPK pathway, which mediates various cellular

Lipid accumulation in the liver: the first and crucial step in NAFLD

A fatty liver is a consequence of over-accumulation of various lipids, mostly observed in cases of obesity [17]. Several events might ultimately result in a fatty liver, especially in the context of IR: increased FFA delivery owing to increased lipolysis from both visceral and subcutaneous adipose tissue, and/or increased intake of dietary fat; decreased FFA oxidation; increased de novo hepatic lipogenesis (DNL); and decreased hepatic lipid export via very-low-density lipoproteins (VLDL). It

Cytokines and transcription factors as driving forces of inflammation

Obesity is associated with a chronic inflammatory response characterized by abnormal cytokine production, increased synthesis of acute-phase reactants and activation of inflammatory signaling pathways [11]. The contribution of adipocytes as a source of these circulating and systemically active cytokines to obesity and obesity-associated diseases such as NAFLD remains unclear. Obese adipose tissue also contains a higher than normal number of macrophages, comprising an additional source of

Adiponectin

Adiponectin exists as a full-length protein as well as a proteolytic cleavage fragment (globular adiponectin) [64]. Serum levels of adiponectin are reduced in individuals with obesity or T2D, and in states of IR [65], and weight loss and PPARγ activation (e.g. by its ligand TZD) induces adiponectin synthesis 60, 61, 66 (Box 1). Initial studies indicated that adiponectin exerted anti-inflammatory effects on endothelial cells by inhibiting TNFα and NFκB [67]. In obese mice, adiponectin treatment

Concluding remarks

NAFLD has emerged as a worldwide major cause of abnormal liver function and is considered a novel component of the metabolic syndrome. Lipid accumulation in the liver is the early and crucial step in NAFLD manifestation. A fatty liver is usually associated with IR, although some experimental evidence indicates that hepatic steatosis and IR might also exist independently of the other [30]. The pro-inflammatory state in the liver observed in NAFLD is regulated by an imbalance of various

Acknowledgements

H.T. and A.R.M. are supported by the Christian Doppler Research Society.

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