The “Domino effect” in MASLD: The inflammatory cascade of steatohepatitis

Abstract

Metabolic dysfunction‐associated steatotic liver disease (MASLD) is an increasingly common complication of obesity, affecting over a quarter of the global adult population. A key event in the pathophysiology of MASLD is the development of metabolic‐associated steatohepatitis (MASH), which greatly increases the chances of developing cirrhosis and hepatocellular carcinoma. The underlying cause of MASH is multifactorial, but accumulating evidence indicates that the inflammatory process in the hepatic microenvironment typically follows a pattern that can be roughly divided into three stages: (1) Detection of hepatocyte stress by tissue‐resident immune cells including γδ T cells and CD4−CD8− double‐negative T cells, followed by their secretion of pro‐inflammatory mediators, most notably IL‐17A. (2) Recruitment of pro‐inflammatory cells, mostly of the myeloid lineage, and initiation of inflammation through secretion of effector‐type cytokines such as TNF, TGF‐β, and IL‐1β. (3) Escalation of the inflammatory response by recruitment of lymphocytes including Th17, CD8 T, and B cells leading to chronic inflammation, hepatic stellate cell activation, and fibrosis. Here we will discuss these three stages and how they are consecutively linked like falling domino tiles to the pathophysiology of MASH. Moreover, we will highlight the clinical potential of inflammation as a biomarker and therapeutic target for the treatment of MASLD.

Underlying Mechanisms behind the Brain–Gut–Liver Axis and Metabolic-Associated Fatty Liver Disease (MAFLD): An Update

“…Thus, it is concluded that the low chronic inflammatory level in adipose tissue, perpetuated due to the accumulation of fat-lipogenesis-which contributes to the accentuation of obesity, contributes to the establishment of the pathogenesis of metabolic disorders, such as MAFLD [176,177]. In this sense, the inflammatory process in adipose tissue is characterized by the infiltration of macrophages and activation of inflammatory pathways mediated mainly by NF-κB and by adipokines, hepatokines, and myokines by endocrine, autocrine, and paracrine pathways, correlating with high serum levels of pro-inflammatory adipokines, such as leptin and resistin, low concentrations of anti-inflammatory adipokines, such as adiponectin, vaspin, and omentin, and high levels of hepatokines (fetuin-A) and pro-inflammatory myokines (irisin and IL-6), constituting the profile of organokines in the context of obesity [178,179].…”