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  • Review Article
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Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies

Nature Reviews Drug Discovery volume 15, pages 249–274 (2016)Cite this article

Subjects

Key Points

  • Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease, encompasses a histological spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), the latter of which has varying degrees of fibrosis. NASH can progress to cirrhosis and is projected to be the leading cause of liver transplantation by 2020. There is no approved therapy for NASH.

  • Several pharmacological strategies for NASH treatment, reflecting putative pathogenic mechanisms, are at the preclinical or early clinical stages of development, and include the modulation of nuclear transcription factors, reversal of lipotoxicity and oxidative stress, and modulation of cellular energy homeostasis and metabolism.

  • In parallel to these metabolic approaches, there is increasing evidence that numerous noxae that initiate liver disease converge to common, stereotyped patterns of injury, inflammation and fibrogenesis in NASH. Molecular mechanisms mediating cell injury and inflammation are also targeted by experimental therapies, including modulation of the inflammasome, chemokines and eicosanoids.

  • An important advance in our knowledge of liver diseases is the understanding that the most advanced stages of fibrosis (and even cirrhosis itself) are part of a dynamic process that may regress if the underlying fibrogenic stimuli are corrected. On this basis, several therapeutic strategies targeting key pathogenic mechanisms involved in fibrogenesis are being evaluated, including inhibitors of galectin 3, leukotrienes, caspases, Hedgehog signalling and lysyl oxidase-like 2 (LOXL2).

  • Collectively, these promising pharmacological strategies may become the armamentarium for an individualized treatment of NASH, targeting the predominant pathogenic mechanisms that operate in each patient and at each stage of disease.

  • Future randomized trials — of adequate power and duration, and with appropriate clinical outcomes — are needed to assess the long-term effectiveness and safety of each pharmacological option.

Abstract

Non-alcoholic fatty liver disease — the most common chronic liver disease — encompasses a histological spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Over the next decade, NASH is projected to be the most common indication for liver transplantation. The absence of an effective pharmacological therapy for NASH is a major incentive for research into novel therapeutic approaches for this condition. The current focus areas for research include the modulation of nuclear transcription factors; agents that target lipotoxicity and oxidative stress; and the modulation of cellular energy homeostasis, metabolism and the inflammatory response. Strategies to enhance resolution of inflammation and fibrosis also show promise to reverse the advanced stages of liver disease.

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Figure 1: Ceramide synthesis and the pathogenesis of non-alcoholic steatohepatitis.
Figure 2: The inflammasome and its involvement in initiation of inflammation.
Figure 3: Chemokines in the pathogenesis of non-alcoholic steatohepatitis.
Figure 4: The self-resolving inflammatory process in the liver.

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  1. Giovanni Musso and Maurizio Cassader: These authors contributed equally to this work.

Authors and Affiliations

  1. Gradenigo Hospital, Corso Regina Margherita 8, Turin, 10132, Italy

    Giovanni Musso

  2. Department of Medical Sciences, University of Turin, Corso A.M. Dogliotti 14, 10126, Turin, Italy

    Maurizio Cassader & Roberto Gambino

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  1. Giovanni Musso
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Correspondence to Giovanni Musso.

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Supplementary information

Supplementary information S1 (table)

Mechanisms of action of natural antioxidants for the treatment of NAFLD (panel A) and main studies assessing the effect of resveratrol on markers of NAFLD (panel B). (PDF 245 kb)

Glossary

Steatosis

Hepatic fatty infiltration in which the total fat content of the liver exceeds 5%.

Steatohepatitis

A liver disease characterized by steatosis, inflammation, ballooning and degeneration of hepatocytes and varying degrees of fibrosis.

Cirrhosis

A condition caused by long-standing liver injury from a variety of causes, which results in liver dysfunction, liver scarring with perturbed architecture and portal hypertension.

Hepatic stellate cell

A liver-resident cell that is predominantly responsible for liver fibrosis.

Methionine–choline-deficient diet

A dietary model of non-alcoholic steatohepatitis (NASH) that involves the administration of a diet with low levels of methionine and choline. Unlike other models of NASH, mice fed a methionine–choline-deficient diet do not develop insulin resistance.

Nonparenchymal cells

Liver cells other than hepatocytes, including different populations of immune, inflammatory and pro-fibrogenic cells.

M1 phenotype

One of two distinct functional states of polarized macrophage activation, the M1 macrophage subtype shows a 'pro-inflammatory' cytokine and chemokine profile.

M2 phenotype

One of two distinct functional states of polarized macrophage activation, the M2 macrophage has an 'anti-inflammatory' cytokine and chemokine profile and is involved in immunosuppression and tissue repair. Importantly, in vitro, macrophages are capable of complete repolarization from M2 to M1 and can change again in response to fluctuations in the cytokine environment. The change in polarization is rapid and alters gene expression, protein and metabolite levels and microbicidal activity.

Inflammasome

A multiprotein oligomer consisting of caspase 1, pyrin domain- and CARD-containing protein (PYCARD), a NOD-, LRR- and pyrin domain-containing protein and sometimes caspase 5 (also known as caspase 11). The exact composition of an inflammasome depends on which activator initiates inflammasome assembly. The inflammasome promotes the maturation of the inflammatory cytokines interleukin 1β (IL-1β) and IL-18 and is responsible for the activation of inflammatory processes in diverse cell lines.

Epithelial-to-mesenchymal transition

A cellular process in which epithelial ductular-like cells disassemble the cell-to-cell attachments that tether them to adjacent cells and acquire a mesenchymal phenotype that allows them to migrate into the stroma, proliferate and synthesize extracellular matrix in response to various growth factors and cytokines.

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Musso, G., Cassader, M. & Gambino, R. Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies. Nat Rev Drug Discov 15, 249–274 (2016). https://doi.org/10.1038/nrd.2015.3

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