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Abstract Details
Treating inflammation to combat non-alcoholic fatty liver disease
J Endocrinol. 2022 Oct 1;JOE-22-0194. doi: 10.1530/JOE-22-0194.Online ahead of print.
1L Wiering, Gastroenterolgy and Hepatology, Charite Universitatsmedizin Berlin, Berlin, Germany.
2F Tacke, Gastroenterolgy and Hepatology, Charite Universitatsmedizin Berlin, Berlin, Germany.
Abstract
Non-alcoholic fatty liver disease (NAFLD) with its more progressive form non-alcoholic steatohepatitis (NASH) has become the most common chronic liver disease, thereby representing a great burden for patients and health care systems. Specific pharmacological therapies for NAFLD are still missing. Inflammation is an important driver in NASH pathogenesis, and the mechanisms underlying inflammation in NAFLD represent possible therapeutic targets. In NASH, various intra- and extrahepatic triggers involved in the metabolic injury typically lead to activation of different immune cells. This includes hepatic Kupffer cells, i.e. liver-resident macrophages, which can adopt an inflammatory phenotype and activate other immune cells by releasing inflammatory cytokines. As inflammation progresses, Kupffer cells are increasingly replaced by monocyte-derived macrophages with a distinct lipid-associated and scar-associated phenotype. Many other immune cells, including neutrophils, T lymphocytes - such as auto-aggressive cytotoxic as well as regulatory T cells - and innate lymphoid cells balance progression and regression of inflammation and subsequent fibrosis. The detailed understanding of inflammatory cell subsets and their activation pathways prompted preclinical and clinical exploration of potential targets in NAFLD/NASH. These approaches to target inflammation in NASH include inhibition of immune cell recruitment via chemokine receptors (e.g. cenicriviroc), neutralization of CD44 or galectin-3 as well as agonism to nuclear factors like peroxisome proliferator-activated receptors (PPAR) and farnesoid X receptor (FXR) that interfere with the activation of immune cells. As some of these approaches did not demonstrate convincing efficacy as monotherapies, a rational and personalized combination of therapeutic interventions may be needed for the near future.