Fibrogenic Pathways in Metabolic Dysfunction Associated Fatty Liver Disease (MAFLD)

Abstract

The prevalence of nonalcoholic fatty liver disease (NAFLD), recently also re-defined as metabolic dysfunction associated fatty liver disease (MAFLD), is rapidly increasing, affecting ~25% of the world population. MALFD/NAFLD represents a spectrum of liver pathologies including the more benign hepatic steatosis and the more advanced non-alcoholic steatohepatitis (NASH). NASH is associated with enhanced risk for liver fibrosis and progression to cirrhosis and hepatocellular carcinoma. Hepatic stellate cells (HSC) activation underlies NASH-related fibrosis. Here, we discuss the profibrogenic pathways, which lead to HSC activation and fibrogenesis, with a particular focus on the intercellular hepatocyte–HSC and macrophage–HSC crosstalk.

N-Octyl Caffeamide, a Caffeic Acid Amide Derivative, Prevents Progression of Diabetes and Hepatic Steatosis in High-Fat Diet Induced Obese Mice

“…Liver is the core organ that regulates glucose and lipid metabolism. Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases and encompasses a wide range of downstream pathologies, including simple steatosis, steatohepatitis, advanced fibrosis, and cirrhosis [ 43 , 44 , 45 ]. After consumption of a high carbohydrate diet, patients with insulin resistance present lower glucose uptake and glycogen synthesis in skeletal muscle, leading to a doubling of both liver triglyceride levels and hepatic de novo lipogenesis [ 46 , 47 ].…”

Hepatic Stellate Cells: Dictating Outcome in Nonalcoholic Fatty Liver Disease

“… 78 Several toxic lipids, such as fatty acids, cholesterol, oxidized low-density lipoproteins, and others, promote macrophage activation, upregulate their proinflammatory phenotype, induce hepatic stellate cell activation (either directly or indirectly via increased inflammation, Figure 1 ), and promote NASH pathogenesis. 79 , 80 , 81 , 82 Free cholesterol is a key lipotoxic molecule in the context of NASH. 81 , 83 In animal models of NAFLD, several studies have demonstrated the importance of dietary cholesterol in promoting inflammation, fibrosis, and NASH pathogenesis.…”

The complex function of macrophages and their subpopulations in metabolic injury associated fatty liver disease

“…Specifically, myeloid cell-specific IRF5-deficient mice are protected from metabolic stress-induced liver fibrosis and exhibit an immunosuppressive and anti-apoptotic transcriptional programme (Alzaid et al, 2016). Furthermore, macrophage derived galectin-3 promotes HSC activation (Subramanian et al, 2022). Galectin-3 is required for TGFβ-dependent HSC activation; in a toxin-induced Under homeostatic conditions, the liver resident KCs exhibit self-renewal capacity, are located in close proximity to the LSECs, express the markers CLEC4F, TIM4 and CLEC2 and exert homeostatic actions.…”

“…Hepatocyte death, a process fostering macrophage recruitment and activation, also drives HSC activation and fibrosis development during NASH (Subramanian et al., 2022). Following hepatocyte death, macrophages clear the apoptotic cells via efferocytosis, which initiates resolution of inflammation pathways (Kourtzelis et al., 2020).…”