Mohammad Shafi Kuchay1, Narendra Singh Choudhary2, Sunil Kumar Mishra3. 1. Division of Endocrinology and Metabolism, Medanta the Medicity Hospital, Gurugram, 122001, Haryana, India. Electronic address: drshafikuchay@gmail.com. 2. Institute of Digestive and Hepatobiliary Sciences, Medanta-The Medicity Hospital, Gurugram, 122001, Haryana, India. 3. Division of Endocrinology and Metabolism, Medanta the Medicity Hospital, Gurugram, 122001, Haryana, India.
Abstract
BACKGROUND AND AIMS: The pathophysiology underlying metabolic associated fatty liver disease (MAFLD) involves a multitude of interlinked processes, including insulin resistance (IR) underlying the metabolic syndrome, lipotoxicity attributable to the accumulation of toxic lipid species, infiltration of proinflammatory cells causing hepatic injury and ultimately leading to hepatic stellate cell (HSC) activation and fibrogenesis. The proximal processes, such as IR, lipid overload and lipotoxicity are relatively well established, but the downstream molecular mechanisms, such as inflammatory processes, hepatocyte lipoapoptosis, and fibrogenesis are incompletely understood. METHODS: A literature search was performed with Medline (PubMed), Scopus and Google Scholar electronic databases till June 2020, using relevant keywords (nonalcoholic fatty liver disease; metabolic associated fatty liver disease; nonalcoholic steatohepatitis; NASH pathogenesis) to extract relevant studies describing pathogenesis of MAFLD/MASH. RESULTS: Several studies have reported new concepts underlying pathophysiology of MAFLD. Activation of HSCs is the common final pathway for diverse signals from damaged hepatocytes and proinflammatory cells. Activated HSCs then secrete excess extracellular matrix (ECM) which accumulates and impairs structure and function of the liver. TAZ (a transcriptional regulator), hedgehog (HH) ligands, transforming growth factor-β (TGF-β), bone morphogenetic protein 8B (BMP8B) and osteopontin play important roles in activating these HSCs. Dysfunctional gut microbiome, dysregulated bile acid metabolism, endogenous alcohol production, and intestinal fructose handling, modify individual susceptibility to MASH. CONCLUSIONS: Newer concepts of pathophysiology underlying MASH, such as TAZ/Ihh pathway, extracellular vesicles, microRNA, dysfunctional gut microbiome and intestinal fructose handling present promising targets for the development of therapeutic agents.
BACKGROUND AND AIMS: The pathophysiology underlying metabolic associated fatty liver disease (MAFLD) involves a multitude of interlinked processes, including insulin resistance (IR) underlying the metabolic syndrome, lipotoxicity attributable to the accumulation of toxic lipid species, infiltration of proinflammatory cells causing hepatic injury and ultimately leading to hepatic stellate cell (HSC) activation and fibrogenesis. The proximal processes, such as IR, lipid overload and lipotoxicity are relatively well established, but the downstream molecular mechanisms, such as inflammatory processes, hepatocyte lipoapoptosis, and fibrogenesis are incompletely understood. METHODS: A literature search was performed with Medline (PubMed), Scopus and Google Scholar electronic databases till June 2020, using relevant keywords (nonalcoholic fatty liver disease; metabolic associated fatty liver disease; nonalcoholic steatohepatitis; NASH pathogenesis) to extract relevant studies describing pathogenesis of MAFLD/MASH. RESULTS: Several studies have reported new concepts underlying pathophysiology of MAFLD. Activation of HSCs is the common final pathway for diverse signals from damaged hepatocytes and proinflammatory cells. Activated HSCs then secrete excess extracellular matrix (ECM) which accumulates and impairs structure and function of the liver. TAZ (a transcriptional regulator), hedgehog (HH) ligands, transforming growth factor-β (TGF-β), bone morphogenetic protein 8B (BMP8B) and osteopontin play important roles in activating these HSCs. Dysfunctional gut microbiome, dysregulated bile acid metabolism, endogenous alcohol production, and intestinal fructose handling, modify individual susceptibility to MASH. CONCLUSIONS: Newer concepts of pathophysiology underlying MASH, such as TAZ/Ihh pathway, extracellular vesicles, microRNA, dysfunctional gut microbiome and intestinal fructose handling present promising targets for the development of therapeutic agents.
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