The pathophysiology of MASLD: an immunometabolic perspective

ABSTRACT

Introduction

Metabolic-associated liver diseases have emerged pandemically across the globe and are clinically related to metabolic disorders such as obesity and type 2 diabetes. The new nomenclature and definition (i.e. metabolic dysfunction-associated steatotic liver disease – MASLD; metabolic dysfunction-associated steatohepatitis – MASH) reflect the nature of these complex systemic disorders, which are characterized by inflammation, gut dysbiosis and metabolic dysregulation. In this review, we summarize recent advantages in understanding the pathophysiology of MASLD, which we parallel to emerging therapeutic concepts.

Areas covered

We summarize the pathophysiologic concepts of MASLD and its transition to MASH and subsequent advanced sequelae of diseases. Furthermore, we highlight how dietary constituents, microbes and associated metabolites, metabolic perturbations, and immune dysregulation fuel lipotoxicity, hepatic inflammation, liver injury, insulin resistance, and systemic inflammation. Deciphering the intricate pathophysiologic processes that contribute to the development and progression of MASLD is essential to develop targeted therapeutic approaches to combat this escalating burden for health-care systems.

Expert opinion

The rapidly increasing prevalence of metabolic dysfunction-associated steatotic liver disease challenges health-care systems worldwide. Understanding pathophysiologic traits is crucial to improve the prevention and treatment of this disorder and to slow progression into advanced sequelae such as cirrhosis and hepatocellular carcinoma.

KEYWORDS:

• Metabolic dysfunction-associated steatotic liver disease
• MASLD
• non-alcoholic fatty liver disease
• NAFLD
• liver injury
• inflammation
• lipotoxicity
• gut-liver axis

Article highlights

• Recently, the terminology and definition of nonalcoholic fatty liver disease was reevaluated and the term metabolic-dysfunction associated steatotic liver disease (MASLD) established, reflecting the origin and pathophysiology of the disease.

• MASLD is strongly associated with other metabolic diseases like type 2 diabetes or obesity, sharing similarities in pathophysiologic traits.

• The gut microbiome and associated metabolites, nutrients, metabolic tissue-derived molecules, and the immune system are implicated in the genesis of MASLD, suggesting an intricate systemic network that drives disease progression toward advanced stages of the diseases such as steatohepatitis, cirrhosis, and malignancy (Figure 1).

• Hyper-anabolism is a cornerstone in the pathomechanism of MASLD, affecting the gut microbiome, metabolic active tissues, and the immune system.

Declaration of interests

The authors have no 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

T.E. Adolph is supported by the Austrian Science Fund (FWF P33070) and the European Research Council (ERC-STG: 101039320). J. Schwärzler is grateful for the support from the Austrian Society of Gastroenterology & Hepatology (ÖGGH) and the Tyrolean Science Funds (TWF F.45107/8-2022). H.Tilg received funding through the excellence initiative (Competence Centers for Excellent Technologies – COMET) of the Austrian Research Promotion Agency FFG: Research Center of Excellence in Vascular Ageing Tyrol, VASCage (K-Project Nr. 843536) funded by the BMVIT, BMWFW, the Wirtschaftsagentur Wien, and the Standortagentur Tirol.