Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)—A Condition Associated with Heightened Sympathetic Activation

Abstract

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease affecting a quarter of the global population and is often associated with adverse health outcomes. The increasing prevalence of MAFLD occurs in parallel to that of metabolic syndrome (MetS), which in fact plays a major role in driving the perturbations of cardiometabolic homeostasis. However, the mechanisms underpinning the pathogenesis of MAFLD are incompletely understood. Compelling evidence from animal and human studies suggest that heightened activation of the sympathetic nervous system is a key contributor to the development of MAFLD. Indeed, common treatment strategies for metabolic diseases such as diet and exercise to induce weight loss have been shown to exert their beneficial effects at least in part through the associated sympathetic inhibition. Furthermore, pharmacological and device-based approaches to reduce sympathetic activation have been demonstrated to improve the metabolic alterations frequently present in patients with obesity, MetSand diabetes. Currently available evidence, while still limited, suggests that sympathetic activation is of specific relevance in the pathogenesis of MAFLD and consequentially may offer an attractive therapeutic target to attenuate the adverse outcomes associated with MAFLD.

The Liver and Heart: How the Two Most Beloved “Babies” in the Human Body Communicate

“…A very recent study identified a liver-heart axis, showing that hepatocyte-derived, rather than locally synthesized, cardiac angiotensinogen, contributes to myocardial dysfunction in septic mouse models [11] . Compelling evidence from animal and human studies suggests that heightened activation of the SNS is a key contributor to the development of NAFLD [12] . This lipolytic state, induced by sympathetic overactivity, results in increased levels of FFAs and triglycerides in the circulation and visceral deposition, which exacerbates NAFLD.…”

“…[11] Compelling evidence from animal and human studies suggests that heightened activation of the SNS is a key contributor to the development of NAFLD. [12] This lipolytic state, induced by sympathetic overactivity, results in increased levels of FFAs and triglycerides in the circulation and visceral deposition, which exacerbates NAFLD.…”

“…Some examples include peroxisome proliferator-activated receptor agonists, known as thiazolidinediones; insulin sensitizing agents, such as metformin; antioxidants, such as vitamin E (a lipophilic antioxidant); and the use of omega-3 polyunsaturated fatty acids and lipid lowering medications, such as fibrates and statins. [12] Currently, there is no specific form of treatment that can meet adequate safety and efficacy standards for both NAFLD and CVD. Therefore, understanding the "crosstalk" between the liver and the cardiovascular system will aid in developing a therapeutic strategy to terminate the vicious circuits that perpetuate NAFLD progression and CVD complications.…”

Circulating level of fatty acid‐binding protein 4 is an independent predictor of metabolic dysfunction‐associated fatty liver disease in middle‐aged and elderly individuals

“…It has also been reported that treatment with FABP4 exogenously induces endoplasmic reticulum stress in HepG2 liver cells as a potential link between hepatic insulin resistance and obesity-associated metabolic dysfunction 37 , suggesting that circulating FABP4 directly affects liver dysfunction, resulting in the development of MAFLD. Conversely, the condition of MAFLD might increase circulating FABP4 concentration through augmentation of catecholamineinduced lipolysis in adipose tissue, since chronic liver disease has been reported to increase sympathetic nervous system activation 38 . These findings indicate that circulating FABP4, derived from not only adipose tissue but also some hepatic cells, is one of the key modulators of MAFLD.…”

Non-alcoholic fatty liver disease (NAFLD) and mental illness: Mechanisms linking mood, metabolism and medicines

“…The liver is regulated by both sympathetic and parasympathetic innervation, and the autonomic nervous system coordinates and regulates diverse hepatic physiology including glucose and liver metabolism, fluid balance, hepatic blood flow, bile flow, hepatic fibrosis and regeneration as well as circadian regulation of liver function ( Jensen et al, 2013 ; Amir et al, 2020 ; Ishay et al, 2021 ; Mizuno et al, 2021 ). The sympathetic nervous system has also been implicated in the pathophysiology of obesity, insulin resistance/metabolic syndrome ( Moreira et al, 2015 ; Guarino et al, 2017 ; Carnagarin et al, 2019 ; Russo et al, 2021 ; Yu and Lee, 2021 ), and emerging data from both pre-clinical and clinical studies suggest that sympathetic nervous system activation contributes to the development of NAFLD ( Carnagarin et al, 2021 ).…”