The molecular basis for current targets of NASH therapies

ABSTRACT

Introduction: Nonalcoholic steatohepatitis (NASH) is a leading cause of liver disease in children and adults, a major contributor to health-care expenditures, and now a leading reason for liver transplantation. Adopting lifestyle modifications with regular exercise and a focus on healthy eating habits is the primary recommendation. However, patients are often unable to achieve and sustain such changes for a variety of social, physical, psychological and genetic reasons. Thus, treatments that can prevent and reverse NASH and its associated fibrosis are a major focus of current drug development.

Areas covered: This review covers the current understanding of lipotoxic liver injury in the pathogenesis of NASH and how lifestyle modification and the spectrum of drugs currently in clinical trials address the many pathways leading to the phenotype of NASH.

Expert opinion: Contrary to the frequently expressed nihilistic view of our understanding of NASH and disappointment with clinical trial results, much is known about the pathogenesis of NASH and there is much reason to be optimistic that effective therapies will be identified in the next 5–10 years. Achieving this will require continued refinement of clinical trial endpoints, continued engagement of trial sponsors and regulatory authorities, and continued participation of dedicated patients in clinical trials.

KEYWORDS:

• Lipotoxicity
• treatment
• insulin resistance
• energy efficiency
• de novo lipogenesis
• fibrogenesis

Article Highlights

• NASH is associated with hepatic fibrosis which may advance to cirrhosis and liver cancer. In comparison, fat accumulation in the liver without substantial inflammation or ballooning, also known as nonalcoholic fatty liver (NAFL), is thought to be a more benign condition which may not progress to NASH.

• NASH is considered a progressive form of nonalcoholic fatty liver disease (NAFLD) and warrants consideration for pharmacotherapy when lifestyle modifications are not achieved and sustained.

• Preclinical studies and clinical trials have established a model of substrate overload lipotoxic liver injury as the cause of NASH. This model facilitates the identification of potential therapeutic interventions and highlights areas where combination therapy is rational. Notably, the accumulation of triglyceride, one of the hallmark features of NASH, is likely an epiphenomenon or adaptive/protective response rather than an essential component of the pathogenesis of NASH.

• NASH is a heterogeneous disease and likely has different underlying contributing factors in different patients. The implications of this are that no single therapy is likely to be effective in all patients and we need a better understanding of the genotype-phenotype correlations to develop targeted precision medicine.

• Treatment approaches currently being investigated are directed at most components of the pathophysiology of NASH, from modulating energy intake to increasing extra-hepatic energy expenditure to diminishing the burden of fatty acids trafficking through the liver, to diminishing the inflammatory and profibrotic effects of lipotoxic injury in the liver.

• The best therapies for NASH, if they can be achieved, may be those that address the most proximal causes of energy overload by altering satiety mechanisms and increasing energy disposal by diminishing energy efficiency. Such approaches might not only be effective in treating NASH but also addressing the other components of the metabolic syndrome.

This box summarizes the key points contained in the article.

Declaration of interest

BA Neuschwander-Tetri has consulting or advisory relationships with Allergan, Allysta, Arrowhead, ARTham, Axcella, Blade, Boehringer Ingelheim, BMS, Coherus, Consynance, Cymabay, Durect, Enanta, Fortress, Gelesis, Gilead, High Tide, HistoIndex, Intercept, Lipocine, Madrigal, Medimmune, Merck, Metacrine, Mundipharma, NGM, pH-Pharma, Prometheus, and Siemens. He has also received Institutional research grants from Allergan, BMS, Cirius, Cymabay, Enanta, Galectin, Genfit, Gilead, Intercept, Madrigal, NGM, and Prometheus. 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

This paper was not funded.