Aerobic exercise training in the treatment of NAFLD related fibrosis

Key points

• Physiologically relevant rodent models of NASH that resemble the human condition are limited.
• Exercise training and energy restriction are first line recommendations for the treatment of NASH.
• Hyperphagic OLETF rats fed a Western diet high in fat, sucrose, and cholesterol for 24 weeks developed a severe NASH with fibrosis phenotype.
• Moderate intensity exercise training and modest energy restriction provided some improvement in the histological features of NASH that coincided with alterations in markers of hepatic stellate cell activation and extracellular matrix remodelling.
• This study highlights the importance of lifestyle modification, including exercise training and energy restriction, in the regulation of advanced liver disease.

Abstract

Nonalcoholic steatohepatitis (NASH) incidence is rising but the efficacy of lifestyle modifications to improve NASH-related outcomes remains unclear. We hypothesized that a Western diet would induce NASH in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat and that lifestyle modification would improve this condition. Methods: Eight week old Long-Evans Tokushima Otsuka (L) and OLETF (O) rats consumed control (CON; 10% kcal fat, 3.5% sucrose) or Western (WD; 45% kcal fat, 17% sucrose, 1% cholesterol) diets for 24 weeks. At 20 weeks of age, additional WD-fed OLETFs were randomized to sedentary (O-SED), food restricted (O-FR; ∼25% kcal reduction vs. O-SED), or exercise training (O-EX; treadmill running 20 m/min, 15% incline, 60 min/d, 5 d/wk) conditions for 12 weeks. Results: WD induced a NASH phenotype in OLETFs characterized by hepatic fibrosis (collagen 1α1 mRNA and hydroxyproline content, elevated inflammation and NAFLD activity scores, and hepatic stellate cell activation (HSC; α-smooth muscle actin) compared to LETOs. FR and EX modestly improved NASH-related fibrosis markers (FR: hydroxyproline content, P < 0.01; EX: collagen 1α1 mRNA, P < 0.05; both: fibrosis score, P < 0.01) and inflammation (both: inflammation score; FR: IL-1β and TNFα) vs. O-SED. FR reduced HSC activation markers (TGF-β protein and αSMA mRNA), while EX increased the HSC senescence marker CCN1 (P < 0.01 vs. O-SED). Additionally, both FR and EX normalized extracellular matrix remodelling markers to levels similar to L-WD (P > 0.05). Conclusion: While neither EX or FR led to complete resolution of the WD-induced NASH phenotype, both independently benefitted liver fibrosis through altered hepatic stellate cell activation and extracellular matrix remodelling.

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