Mechanisms and Therapeutic Strategies for MAFLD Targeting TLR4 Signaling Pathways

Abstract

Background: Metabolic-associated fatty liver disease (MAFLD) is one of the most common chronic liver diseases. The underlying pathophysiological mechanisms are intricate and involve various factors. Unfortunately, there is currently a lack of available effective treatment options. Toll-like receptors (TLRs) are a group of pattern-recognition receptors that are responsible for activating the innate immune system. Research has demonstrated that TLR4 plays a pivotal role in the progression of MAFLD by facilitating the pathophysiological mechanisms. Summary: Lipid peroxidation, pro-inflammatory, insulin resistance (IR), and dysbiosis of intestinal microbiota are considered as the pathogenic mechanisms of MAFLD. This review summarizes the impact of TLR4 signaling pathways on the progression of MAFLD, specifically in relation to lipid metabolic disorders, IR, oxidative stress, and gut microbiota disorders. Additionally, we emphasize the potential therapeutic approaches for MAFLD that target TLR4 signaling pathways, including the use of plant extracts, traditional Chinese medicines, probiotics, pharmaceuticals such as PPAR antagonists and FXR agonists, and lifestyle modifications such as dietary changes and exercise also considered. Furthermore, TLR4 signaling pathways have also been linked to the lean MAFLD. Key Messages: TLR4 plays a crucial role in MAFLD by triggering insulin resistance, buildup of lipids, imbalance in gut microbiota, oxidative stress, and initiation of immune responses. The mitigation of MAFLD can be accomplished by suppressing the TLR4 signaling pathway. In the future, it could potentially emerge as a therapeutic target for the condition.

Underlying Mechanisms behind the Brain–Gut–Liver Axis and Metabolic-Associated Fatty Liver Disease (MAFLD): An Update

“…Myokines are produced by skeletal muscle in response to muscle contraction and act in an inhibitory way against the harmful effects of pro-inflammatory adipokines [162,163]. Irisin, active in inducing the differentiation of white adipose tissue (WAT) into brown adipose tissue (BAT), suppresses lipogenesis and cholesterol synthesis, optimizing lipid oxidation and, consequently, lipid homeostasis [69,164]. Myostatin and Mionectin act in the progression of lipid uptake and deposition in the liver, in the propensity for the pro-inflammatory scenario, and in the inhibition of antioxidant compounds [43].…”

“…SIRT1, in humans with MAFLD, presents reduced regulation associated with increased expression of lipogenic proteins, such as Sterol Regulatory Element Binding Protein 1 (SREBP1), Acetyl-CoA Carboxylase (ACC), and Fas Cell Surface Death Receptor (FAS). Next, the lack of SIRT1 catalytic activity promotes the excretion of free FAs from mesenteric adipose tissue, aggravating MAFLD [164]. Thus, SIRT1 levels are reduced in obese patients and obese patients with severe hepatic steatosis compared with obese patients with mild hepatic steatosis.…”