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. 2018 Dec;17(4):350-360.
doi: 10.1007/s11901-018-0425-7. Epub 2018 Oct 31.

Pathogenesis of NASH: The Impact of Multiple Pathways

Mazen Noureddin  1 , Arun J Sanyal  2
Affiliations

Pathogenesis of NASH: The Impact of Multiple Pathways

Mazen Noureddin et al. Curr Hepatol Rep. 2018 Dec.

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.

Keywords: Nonalcoholic fatty liver disease (NAFLD); Nonalcoholic steatohepatitis (NASH); ROS (reactive oxygen species); cirrhosis; fibrosis; microbiome.

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Figures

Figure 1:
Figure 1:
Pathogenesis of NAFLD/NASH and Contributing Factors
Figure 2:
Figure 2:
Role of Free Fatty Acids in NAFLD/NASH (Lipotoxicity and Glucotoxicity) Abbreviations: FFA: Free Fatty Acid, VLDL: Very low density lipoprotein
See this image and copyright information in PMC

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