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Pathogenesis of NASH: the Impact of Multiple Pathways

  • Fatty Liver Disease (Z Younossi, Section Editor)
  • Published:
Current Hepatology Reports Aims and scope Submit manuscript

Abstract

Purpose of review

Advancing our understanding of the mechanisms that underlie NASH pathogenesis.

Recent findings

Recent findings on NASH pathogenesis have expanded our understanding of its complexity including (1) there are multiple parallel hits that lead to NASH; (2) the microbiota play an important role in pathogenesis, with bacterial species recently shown to accurately differentiate between NAFL and NASH patients; (3) the main drivers of liver cell injury are lipotoxicity caused by free fatty acids (FFAs) and their derivatives combined with mitochondrial dysfunction; (4) decreased endoplasmic reticulum (ER) efficiency with increased demand for protein synthesis/folding/repair results in ER stress, protracted unfolded protein response, and apoptosis; (5) upregulated proteins involved in multiple pathways including JNK, CHOP, PERK, BH3-only proteins, and caspases result in mitochondrial dysfunction and apoptosis; and (6) subtypes of NASH in which these pathophysiological pathways vary may require patient subtype identification to choose effective therapy.

Summary

Recent pathogenesis studies may lead to important therapeutic advances, already seen in patients treated with ACC, ASK1 and SCD1 inhibitors, and FXR agonists. Further, advancing our understanding of mechanisms underlying NASH pathogenesis and the complex interplay between them will be crucial for developing effective therapies.

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Authors and Affiliations

  1. Division of Digestive and Liver Diseases, Comprehensive Transplant Program, Cedars-Sinai Medical Center, CA, Los Angeles, USA

    Mazen Noureddin

  2. Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, P.O. BOX 980341, Richmond, VA, USA

    Arun J. Sanyal

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  1. Mazen Noureddin
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Correspondence to Arun J. Sanyal.

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Conflicts of Interest

Arun J. Sanyal reports grants and other from Gilead, grants from Intercept, grants and other from Novartis, grants from Merck, grants and other from BMS, grants from Tobira, grants from Echosense, other from Sanyal Bio, other from Genfit, other from Tiziana, other from Galectin, other from Nitto Denko, other from Nimbus, other from Aredlyx, other from Vivelyx, other from Teva, other from Canfite, other from Boehringer Ingelheim, other from Pfizer, other from Salix, other from Enyo, other from uptodate, other from Natural Shield, other from Durect, other from Exhalenz, other from Hemoshear, and other from Akarna, outside the submitted work. Mazen Noureddin has been on the advisory board or a speaker for EchoSens North America, OWL, Gilead, Intercept, Novartis and Allergan. He has been a speaker for: Simply Speaking, Echosens, Alexion and Abbott. He has received research support from: Allergan, Gilead, Galmed, Galectin, Genfit, Conatus, Intercept, Enanta, Zydus, and Shire; Mazen Noureddin is a minor shareholder of Anaetos.

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Noureddin, M., Sanyal, A.J. Pathogenesis of NASH: the Impact of Multiple Pathways. Curr Hepatology Rep 17, 350–360 (2018). https://doi.org/10.1007/s11901-018-0425-7

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