Beyond insulin resistance: Innate immunity in nonalcoholic steatohepatitis

Abstract

Obesity is an inflammatory disorder characterized by heightened activity of the innate immune system. Innate immune activation is central to the development of obesity-related insulin resistance; it also plays an important role in obesity-related tissue damage, such as that seen in atherosclerosis. Recent research has implicated the innate immune system in the pathophysiology of obesity-related liver disease. This review summarizes how innate immune processes, occurring both within and outside the liver, cause not only insulin resistance but also end-organ damage in the form of nonalcoholic fatty liver disease.

Fig. 1

Activation of inflammatory signaling pathways by fat. Excess fat or fatty acids (FA) can activate a number of intracellular signaling pathways that lead to inflammation through IKK and JNK IKK and JNK cause inflammation by promoting formation of the transcription factors AP-1 and NF-κB, which activate transcription of a host of proinflammatory genes including cytokines, chemokines, and cell adhesion molecules. PKC, IKK and JNK can also cause insulin resistance by promoting aberrant serine phosphorylation of IRS-1 and IRS-2. (1) The lipid intermediate diacylglycerol (DAG), formed during the synthesis or hydrolysis of triacylglycerol (TAG), can activate PKC, which causes downstream activation of IKK and JNK. (2) Fatty acid oxidation yields reactive oxygen species (ROS), which can directly activate IKK and JNK. (3) Excess fat can promote ER stress, which activates IKK and JNK through the intermediate kinases IRE-1 and PERK. (4) Extracellular fatty acids can act as ligands for TLR, which signal through IKK and JNK.

Fig. 2

Proposed mechanisms of adipose tissue macrophage activation and their contribution to NAFLD. (A) Normal adipose tissue contains a small number of resident macrophages with an M2 (anti-inflammatory) phenotype. Expansion of adipocytes with fat in obesity can provoke adipocyte necrosis, with the released cellular debris and free fatty acids (FFA) activating resident macrophages and signaling the recruitment of M1 (proinflammatory) macrophages from the circulation. The resulting inflamed fat produces high levels of TNFα and MCP-1 and low levels of adiponectin, which can contribute to NAFLD. TNFα and MCP-1 can derive from both adipocytes and macrophages, whereas adiponectin is produced exclusively by adipocytes. (B) Obese adipocytes remain viable but are induced to secrete MCP-1, CXCL14, and perhaps osteopontin. This attracts and activates macrophages to an M1 phenotype. The end result is the same, with inflamed fat producing high levels of TNFα and MCP-1 and low levels of adiponectin.