Emerging therapeutic targets for NASH: key innovations at the preclinical level

ABSTRACT

Introduction: nonalcoholic steatohepatitis (NASH) is a globally emerging health problem, mainly caused by increasing trends in the prevalence of obesity and metabolic syndrome. Patients with NASH are mainly affected by cardiovascular risk and extrahepatic cancer, but a significant proportion of patients will develop advanced liver disease, eventually resulting in liver failure or hepatocellular carcinoma. Recent research has yielded a better understanding of the underlying mechanisms and potential targetability for drug development.

Areas covered: This review focuses on the role of fructose metabolism, de novo lipogenesis (DNL), endoplasmic reticulum (ER) stress, NLRP3 inflammasome, bone morphogenetic protein (BMP) signaling and platelets in the pathophysiology of NASH. We discuss the suitability of these substrates for targeting liver disease as well as cardiovascular health in patients with NASH. A non-systematic literature search was performed on PubMed and ClinicalTrials.gov.

Expert opinion: Targeting fructose metabolism, DNL, ER stress, NLRP3 inflammasome, BMP signaling and platelets are promising therapeutic strategies, warranting further preclinical and clinical investigation. The discussed approaches might not only benefit liver-related outcomes but improve cardiovascular disease as well. Amidst the euphoria of advances in drug development for NASH, parallel endeavors need to address the underlying causes of obesity and metabolic syndrome to prevent NASH.

KEYWORDS:

• Bone-morphogenetic proteins
• endoplasmic reticulum stress
• inflammasome
• lipid metabolism
• nonalcoholic fatty liver disease
• nonalcoholic steatohepatitis
• platelets
• pyroptosis
• treatment

Article Highlights

• The processes involved in de novo lipogenesis and endoplasmic reticulum stress not only contribute to the development of steatosis but are critical, therapeutically targetable drivers of liver inflammation and fibrosis in NASH

• The NLRP3 inflammasome is critically involved in the progression of NASH and targeting of inflammasome components is already tested in clinical trials.

• Pyroptosis downstream of the NLRP3 inflammasome and gasdermin D, in particular, is a novel potential therapeutic target in NASH

• Platelets have been identified as important players in initiation and perpetuation of liver inflammation and fibrosis in NASH and platelet GPIbα as well as platelet cargo could be a potential target for developing treatments

• Bone morphogenetic protein signalling is involved in many layers of liver homeostasis but the processes are complex and need to be studied in detail for NASH to define suitable therapeutic targets

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Disclaimer

This paper presents independent research funded (or supported) by the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham (Grant Reference Number BRC-1215-20009). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

Declaration of interest

PN Newsome has received consultancy or speaker fees on behalf of the University of Birmingham from Boehringer Ingelheim, Gilead, Pfizer, Affimmune, Intercept, Johnson & Johnson, Novo Nordisk, Shire, and Poxel Pharmaceuticals. His institution receives grant funding from Pharmaxis, Boehringer Ingelheim, and Novo Nordisk. P Horn has engaged in scientific collaboration with Novo Nordisk, Geratherm respiratory GmbH and UST Umweltsensortechnik and funding from Novo Nordisk. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

The work of the authors has received funding from University Hospitals Birmingham NHS Foundation Trust grant [BRC-1215-20009].