How Inflammation Impinges on NAFLD: A Role for Kupffer Cells

Figure 1

Kupffer cells and inflammation in NAFLD. Kupffer cells integrate a multitude of systemic and local stimuli, namely, inflammatory cues from diet-derived alterations in gut microbiota, as well as adipose tissue and hepatocytes signals of lipid metabolism impairments. Subsequent activation of Kupffer cells promotes a local inflammatory milieu that results in exacerbation of steatosis, hepatocyte dysfunction, and fibrogenesis. High-energy diets induce alterations in gut microbiome and increased permeability that result in augmented passage of pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharides (LPS) to the portal vein. PAMPs interact with Kupffer cells through pattern recognition receptors (PRRs), activating innate immunity signal pathways (e.g., Myd88 or inflammasome) leading to the secretion of proinflammatory and profibrogenic cytokines. Increased adiposity and inflammation in adipose tissue caused by high-energy diets induce the release of free fatty acids (FFAs) and adipokines into circulation. FFAs and adipokines may on one hand contribute to Kupffer cell stimulation and on the other hand promote hepatic steatosis through enhanced FFA uptake and/or increase in de novo lipogenesis. Additionally, cytokine release by Kupffer cells sustain hepatic stellate cell differentiation into collagen producing myofibroblast and contribute to hepatocyte metabolic dysfunctions.