Current perspectives on the pathophysiology of metabolic associated fatty liver disease: are macrophages a viable target for therapy?

ABSTRACT

Introduction

Metabolic associated fatty liver disease (MAFLD) is a new nomenclature for fatty liver replacing nonalcoholic fatty liver disease (NAFLD). MAFLD has emerged as the leading cause of liver-related morbidity and mortality with increasing incidence due to its close association with the global epidemic of obesity and type 2 diabetes mellitus.

Macrophages play a key role in MAFLD development and progression of steatohepatitis and fibrosis. Therefore, targeting macrophages may be a new therapeutic approach for MAFLD and MAFLD with steatohepatitis.

Areas covered

We provide a comprehensive review of the significant role of macrophages in MAFLD. Further, we evaluate the current status of lifestyle interventions and pharmacological treatments with a focus on effects mediated through direct or indirect targeting of macrophages.

Expert opinion

Targeting macrophages holds promise as a treatment option for the management of MAFLD and steatohepatitis. Improved stratification of patients according to MAFLD phenotype would contribute to more adequate design enhancing the yield of clinical trials ultimately leading to personalized medicine for patients with MAFLD. Furthermore, reflecting the multifactorial pathogenesis of MAFLD, combination therapies based on the various pathophysiological driver events including as pertinent to this review, macrophage recruitment, polarization and action, present an intriguing target for future investigation.

KEYWORDS:

• CD163
• cirrhosis
• kupffer cells
• macrophages
• metabolic associated fatty liver disease
• NASH
• NAFLD
• nonalcoholic fatty liver disease
• nonalcoholic steatohepatitis

Article highlights

• Liver macrophages are key players in MAFLD development and progression with the resident macrophages (Kupffer cells) initiating a pro-inflammatory response in the early phases of the disease and orchestrating the recruitment of circulating monocytes to the liver

• Liver macrophages may be stimulated by pathogen- (PAMPs) and damage-associated molecular patterns (DAMPs) as well as free fatty acids to promote the transition from simple steatosis to steatohepatitis with inflammation, fibrosis, and ultimately cirrhosis

• These findings place macrophages as an intriguing target for pharmacological intervention in MAFLD and steatohepatitis. Direct targeting of macrophages as well as drugs indirectly affecting macrophage recruitment, polarization, and activation has shown promising results in clinical studies of MAFLD with GLP-1 analogs and FXR antagonists as the most prominent drug candidates

• MAFLD and MAFLD with steatohepatitis are highly complex conditions with several separate but concurring events driving disease progression. Thus, combination therapy with several pharmacological interventions targeting different pathophysiological processes may prove an efficient treatment strategy

Declaration of interest

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

This paper was not funded.