The impact of aerobic and anaerobic exercise interventions on the management and outcomes of non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder that includes non-alcoholic hepatic steatosis without or with moderate inflammation and non-alcoholic steatohepatitis (NASH), characterized by necroinflammation and a more rapid progression of fibrosis. It is the primary pathological basis for hepatocellular carcinoma. With its prevalence escalating annually, NAFLD has emerged as a global health epidemic, presenting a significant hazard to public health worldwide. Existing studies have shown that physical activity and exercise training have a positive effect on NAFLD. However, the extent to which exercise improves NAFLD depends on the type, intensity, and duration. Therefore, the type of exercise that has the best effect on improving NAFLD remains to be explored. To date, the most valuable discussions involve aerobic and anaerobic exercise. Exercise intervenes in the pathological process of NAFLD by regulating physiological changes in cells through multiple signaling pathways. The review aims to summarize the signaling pathways affected by two different exercise types associated with the onset and progression of NAFLD. It provides a new basis for improving and managing NAFLD in clinical practice.

Fig. 1

The positive feedback loop between CNPY2 and the PERK/CHOP axis. Canopy fibroblast growth factor signaling regulator 2 (CNPY2) upregulation elicits an unfolded protein response (UPR). It activates the downstream protein kinase RNA-like endoplasmic reticulum kinase (PERK)/C/EBP homologous protein (CHOP) axis, which in turn promotes CNPY2 transcription. This process upregulates vascular endothelial growth factor (VEGF) and leads to increased endoplasmic reticulum stress (ERS).

Fig. 2

The molecular mechanism of aerobic exercise affects the AMPK axis in hepatocytes. During exercise, a rise in the AMP/ATP ratio promotes AMP-activated protein kinase (AMPK) phosphorylation. It results in peroxisome proliferator-activated receptor α (PPARα) binding at the peroxisome proliferator response elements (PPREs) site, which promotes peroxisome proliferator-activated receptor co-activator-1α (PGC-1α) transcription. It also upregulates carnitine palmitoyl transferase 1 (CPT1) transcription, contributing to lipolysis. Moreover, the AMPK/sirtuin1 (SIRT1) axis improves insulin sensitivity and reduces hepatic steatosis.

Fig. 3

The central pivotal role of SRA in NAFLD occurrence and progression. Steroid receptor RNA activator (SRA) upregulates protein kinase-like endoplasmic reticulum kinase (PERK) and endoplasmic reticulum transmembrane kinase 1α (IRE1α) to promote endoplasmic reticulum stress and inflammation. SRA promotes the phosphorylation of forkhead box protein O1 (FoxO1) to inhibit adipose triglyceride lipase (ATGL) expression, thereby preventing lipolysis. SRA is also involved in steatosis by regulating the p38/C-Jun amino-terminal kinases (JNKs) signaling pathway. p38/JNK is regulated by upstream factors dual-specificity phosphatase 16 (DUSP16) and AMP-activated protein kinase α1 (AMPKα1).