Abstract
Recent lines of evidence highlight the involvement of myeloid-epithelial-reproductive tyrosine kinase (MerTK) in metabolic disease associated with liver damage. MerTK is mainly expressed in anti-inflammatory M2 macrophages where it mediates transcriptional changes including suppression of proinflammatory cytokines and enhancement of inflammatory repressors. MerTK is regulated by metabolic pathways through nuclear sensors including LXRs, PPARs, and RXRs, in response to apoptotic bodies or to other sources of cholesterol. Nonalcoholic fatty liver disease (NAFLD) is one of the most serious public health problems worldwide. It is a clinicopathological syndrome closely related to obesity, insulin resistance, and oxidative stress. It includes a spectrum of conditions ranging from simple steatosis, characterized by hepatic fat accumulation with or without inflammation, to nonalcoholic steatohepatitis (NASH), defined by hepatic fat deposition with hepatocellular damage, inflammation, and accumulating fibrosis. Several studies support an association between NAFLD and the incidence of cardiovascular diseases including atherosclerosis, a major cause of death worldwide. This pathological condition consists in a chronic and progressive inflammatory process in the intimal layer of large- and medium-sized arteries. The complications of advanced atherosclerosis include chronic or acute ischemic damage in the tissue perfused by the affected artery, leading to cellular death. By identifying specific targets influencing lipid metabolism and cardiovascular-related diseases, the present review highlights the role of MerTK in NAFLD-associated atherosclerotic lesions as a potential innovative therapeutic target. Therapeutic advantages might derive from the use of compounds selective for nuclear receptors targeting PPARs rather than LXRs regulating macrophage lipid metabolism and macrophage mediated inflammation, by favoring the expression of MerTK, which mediates an immunoregulatory action with a reduction in inflammation and in atherosclerosis.
Highlights
Specialty section: This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology
Therapeutic advantages might derive from the use of compounds selective for nuclear receptors targeting peroxisome proliferator-activated receptors (PPARs) rather than liver X receptors (LXRs) regulating macrophage lipid metabolism and macrophage mediated inflammation, by favoring the expression of myeloid-epithelial-reproductive tyrosine kinase (MerTK), which mediates an immunoregulatory action with a reduction in inflammation and in atherosclerosis
Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of conditions ranging from simple hepatic lipid accumulation without inflammation, defined nonalcoholic fatty liver or NAFL, to nonalcoholic steatohepatitis (NASH), characterized by hepatic fat deposition with hepatocellular damage, inflammation, and fibrosis
Summary
METABOLIC ASPECTS OF NAFLD: INSULIN RESISTANCE, METABOLIC SYNDROME, AND TYPE 2 DIABETES. Tissue injury induces an inflammatory response involving the local vascular system, immune cells, and release of endocrine and neurological factors In this context, non-parenchymal cells [endothelial and hepatic stellate cells (HSCs)] and resident or recruited immune cells [macrophages, dendritic cells (DCs), and mast cells] secrete a variety of pro-inflammatory molecules such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), pro-fibrotic factors including transforming growth factor-β (TGF-β) and proapoptotic mediators, as well as reactive oxygen species (Tilg and Diehl, 2000). The main alteration in atherogenesis is the TG hepatic overproduction of as well as cholesterol-enriched VLDL particles
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