Semin Liver Dis 2017; 37(03): 189-197
DOI: 10.1055/s-0037-1604480
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Macrophages in Nonalcoholic Fatty Liver Disease: A Role Model of Pathogenic Immunometabolism

Oliver Krenkel1, Frank Tacke1
  • 1Department of Medicine III, University Hospital Aachen, Aachen, Germany
Further Information

Publication History

Publication Date:
28 August 2017 (online)

Abstract

Nonalcoholic fatty liver disease (NAFLD) and its progressive inflammatory form, nonalcoholic steatohepatitis (NASH), are leading causes of liver cirrhosis and hepatocellular carcinoma. Metabolism and inflammation are intimately interrelated in NAFLD/NASH, as expressed by the term immunometabolism. Hepatic macrophages mediate inflammatory responses during metabolic disorders and can stimulate or dismantle liver fibrosis. Their functional diversity is partly explained by heterogeneous macrophage subsets: tissue-resident Kupffer cells and monocyte-derived macrophages. However, macrophages themselves are altered in their functional polarization by dietary composition and metabolic or inflammatory stimuli in NAFLD. The inflammatory polarization of macrophages correlates with changes in core metabolism pathways like oxidative phosphorylation and glycolysis. The availability of nutrients, such as glucose or fatty acids or oxygen also influences macrophage polarization upon danger signal or cytokine reception. Understanding the interplay of metabolism and macrophage function in NASH may open new approaches to therapeutic targeting of these essential modifiers in metabolic liver diseases.

Key Learning Points

• Immunometabolism comprises the modulation of whole body metabolism by immune cells, as well as the link between inflammatory polarization and cell metabolism.


• Hepatic macrophages mediate the onset as well as the progression of NAFLD from steatosis toward steatohepatitis and fibrosis by releasing inflammatory cytokines, chemokines, and reactive oxygen species.


• Inflammatory polarization of macrophages, following toll-like receptor signaling, is associated with a shift from oxidative phosphorylation and fatty acid oxidation toward glycolysis and the pentose phosphate pathway.


• Liver macrophages are interesting therapeutic targets for treating NASH by either promoting an anti-inflammatory polarization of macrophages or by inhibiting the infiltration of inflammatory monocytes.