Liver Fibrosis and MAFLD: From Molecular Aspects to Novel Pharmacological Strategies

Abstract

Metabolic-associated fatty liver disease (MAFLD) is a new disease definition, and this nomenclature MAFLD was proposed to renovate its former name, non-alcoholic fatty liver disease (NAFLD). MAFLD/NAFLD have shared and predominate causes from nutrition overload to persistent liver damage and eventually lead to the development of liver fibrosis and cirrhosis. Unfortunately, there is an absence of effective treatments to reverse MAFLD/NAFLD-associated fibrosis. Due to the significant burden of MAFLD/NAFLD and its complications, there are active investigations on the development of novel targets and pharmacotherapeutics for treating this disease. In this review, we cover recent discoveries in new targets and molecules for antifibrotic treatment, which target pathways intertwined with the fibrogenesis process, including lipid metabolism, inflammation, cell apoptosis, oxidative stress, and extracellular matrix formation. Although marked advances have been made in the development of antifibrotic therapeutics, none of the treatments have achieved the endpoints evaluated by liver biopsy or without significant side effects in a large-scale trial. In addition to the discovery of new druggable targets and pharmacotherapeutics, personalized medication, and combinatorial therapies targeting multiple profibrotic pathways could be promising in achieving successful antifibrotic interventions in patients with MAFLD/NAFLD.

Keywords: cirrhosis; drug target; liver fibrosis; metabolic associated fatty liver disease; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis.

Figure 1

Pathogenetic mechanisms underlying fibrosis in MAFLD/NAFLD and molecular target of drug therapy. There are three sources of hepatic free fatty acids (FFA): 60% from the adipose tissue lipolysis or non-esterified fatty acid (NEFA) pool, 25% from de novo lipogenesis (DNL), and the remaining 15% from the intestinal absorption of diet. The two main metabolic pathways of hepatic FFA are mitochondria-mediated β-oxidation and esterification to form triglyceride (TG). Triglyceride is able to be exported into the circulation in the form of very-low-density lipoprotein (VLDL), and the excessive TG are stored in lipid droplets. When FFA are overaccumulated or their disposal is not timely, the redundant FFA act as substrates to produce lipotoxic lipids, which lead to endoplasmic reticulum (ER) stress, production of reactive oxygen species (ROS), impaired mitochondrial function and release of danger-associated molecular patterns (DAMPs). Pattern recognition receptors such as toll-like receptors (TLRs) sense the continuous production of DAMPs and metabolites, thereby triggering downstream signaling pathways. Apoptosis signal-regulating kinase 1 (ASK1) and TGF-β-activated kinase 1 (TAK1) are crucial intracellular signal transduction components that are activated by post-transcriptional modification, and further activate their downstream pivotal kinases and transcription factors, leading to the occurrence of metabolic inflammation. As metabolic stress leads to the expression and release of inflammatory chemokines, Kupffer cells (KCs) polarize into pro-inflammatory phenotypes and participate in the activation of hepatic stellate cells (HSCs) in coordination with ROS, apoptotic signals and ER stress. These exacerbate extracellular matrix formation and collagen deposition, and result in liver fibrosis. Emerging therapeutic agents and their molecular targets for fibrosis in MAFLD/NAFLD are also indicated. Agonists and analogs are marked in green, while antagonists, inhibitors and antibodies are marked in blue.