Abstract:Nonalcoholic fatty liver disease (NAFLD) is the dominant cause of liver disease worldwide. Nonalcoholic steatohepatitis (NASH), a more aggressive presentation of NAFLD, is characterized by severe hepatocellular injury, inflammation, and fibrosis. Chronic inflammation and heightened immune cell activity have emerged as hallmark features of NASH and key drivers of fibrosis through the activation of hepatic stellate cells (HSCs). Recent advances in our understanding of the molecular and cellular pathways in NASH … Show more
“… 10 Activated hepatic stellate cells secrete a wide range of proinflammatory cytokines, such as CCL2, CCL5, IL8, chemokine (C-X-C motif) ligand-12 (CXCL12), and express adhesion molecules, such as intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 and chemokine receptors (CCR5), resulting in increased recruitment and infiltration of immune cells into the liver. 34 Figure 1 Pathways of hepatic stellate cell activation and survival during NAFLD. Various factors, such as lipid mediators, free cholesterol accumulation, oxLDL, palmitic acid, LPS, and immune cell–derived profibrotic molecules and growth factors, promote hepatic stellate cell activation and survival during NAFLD.…”
Section: Role Of Hepatic Stellate Cells In Nonalcoholic Fatty Liver D...mentioning
“… 10 Activated hepatic stellate cells secrete a wide range of proinflammatory cytokines, such as CCL2, CCL5, IL8, chemokine (C-X-C motif) ligand-12 (CXCL12), and express adhesion molecules, such as intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 and chemokine receptors (CCR5), resulting in increased recruitment and infiltration of immune cells into the liver. 34 Figure 1 Pathways of hepatic stellate cell activation and survival during NAFLD. Various factors, such as lipid mediators, free cholesterol accumulation, oxLDL, palmitic acid, LPS, and immune cell–derived profibrotic molecules and growth factors, promote hepatic stellate cell activation and survival during NAFLD.…”
Section: Role Of Hepatic Stellate Cells In Nonalcoholic Fatty Liver D...mentioning
“…The factors initiating hepatocyte injury in MASH are not yet definitively identified, but several candidates have been proposed. These include dysregulated circulating adipokines and inflammatory molecules [26][27][28][29], elevated circulating insulin and insulin like growth factor (IGF), and signals from the gut microbiome, which exhibits abnormalities in MASH patients and animal models. With the advent of single cell RNA sequencing technologies, subsets of hepatocytes have been identified that may selectively promote the development of MASLD [30].…”
Section: Upstream Drivers Of Hepatocyte Injury In Mashmentioning
Metabolic dysfunction-associated steatotic (fatty) liver disease (MASLD), previously termed non-alcoholic fatty liver disease, is a worldwide epidemic that can lead to hepatic inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The disease is typically a component of the metabolic syndrome that accompanies obesity, and is often overlooked because the liver manifestations are clinically silent until late-stage disease is present (i.e., cirrhosis). Moreover, Asian populations, including Koreans, have a higher fraction of patients who are lean, yet their illness has the same prognosis or worse than those who are obese. Nonetheless, ongoing injury can lead to hepatic inflammation and ballooning of hepatocytes as classic features. Over time, fibrosis develops following activation of hepatic stellate cells, the liver’s main fibrogenic cell type. The disease is usually more advanced in patients with type 2 diabetes mellitus, indicating that all diabetic patients should be screened for liver disease. Although there has been substantial progress in clarifying pathways of injury and fibrosis, there no approved therapies yet, but current research seeks to uncover the pathways driving hepatic inflammation and fibrosis, in hopes of identifying new therapeutic targets. Emerging molecular methods, especially single cell sequencing technologies, are revolutionizing our ability to clarify mechanisms underlying MASLD-associated fibrosis and HCC.
“…Activated hepatic stellate cells (aHSCs) are a key cell-type that drives fibrogenesis in all forms of chronic liver disease, including NAFLD ( 9 ). HSCs comprise approximately 5-10% of the non-parenchymal cell population in the liver ( 10 ).…”
Non-alcoholic fatty liver disease (NAFLD) - characterized by excess accumulation of fat in the liver - now affects one third of the world's population. As NAFLD progresses, extracellular matrix components including collagen accumulate in the liver causing tissue fibrosis, a major determinant of disease severity and mortality. To identify transcriptional regulators of fibrosis, we computationally inferred the activity of transcription factors (TFs) relevant to fibrosis by profiling the matched transcriptomes and epigenomes of 108 human liver biopsies from a deeply-characterized cohort of patients spanning the full histopathologic spectrum of NAFLD. CRISPR-based genetic knockout of the top 100 TFs identified ZNF469 as a regulator of collagen expression in primary human hepatic stellate cells (HSCs). Gain- and loss-of-function studies established that ZNF469 regulates collagen genes and genes involved in matrix homeostasis through direct binding to gene bodies and regulatory elements. By integrating multiomic large-scale profiling of human biopsies with extensive experimental validation we demonstrate that ZNF469 is a transcriptional regulator of collagen in HSCs. Overall, these data nominate ZNF469 as a previously unrecognized determinant of NAFLD-associated liver fibrosis.
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