The “dose” of exercise and its effects beyond weight loss
Authors: Mary E. Rinella
Journal: Hepatology (2014)

Potential conflict of interest: Dr. Rinella consults for AbbVie, FibroGen, Takeda and NGM Biopharmaceuticals. See Article on Page 1205 One of the most onerous challenges we face in the treatment of nonalcoholic fatty liver disease (NAFLD) is that success will depend on our ability to change the behavior of our patients; a lofty goal. NAFLD is a complex metabolic disease that typically occurs in patients who are either overweight or have metabolic consequences of obesity, even if weight is within the normal range. Over a decade of excellent research has taught us that insulin resistance (IR) and visceral obesity in particular promote a milieu that favors the accumulation of liver fat, inflammation, and injury resulting in progressive liver disease and other extrahepatic ailments. Consensus opinion uniformly recommends diet and exercise as the basis of any treatment plan for patients with NAFLD, despite a relative paucity of rigorous evidence in the form of well‐powered randomized, controlled trials to support this. Weight loss has many beneficial effects beyond the liver, and available data do consistently show that weight loss reduces hepatic fat content as well as improves liver enzymes and histological features associated with nonalcoholic steatohepatitis (NASH).1 Exercise also has many known benefits, including reducing cardiovascular risk, which is of particular importance to patients with NAFLD. However, there are less data demonstrating the independent efficacy of exercise in NAFLD, specifically and whether these benefits extend beyond weight loss. Exercise in the absence of associated weight loss has biological plausibility as a potential treatment of NAFLD. Exercise improves cardiovascular health and improves peripheral, adipose, and hepatic IR, independent of weight loss. Most studies that have looked at various types of exercise as an intervention in patients with NAFLD have been small and underpowered. A prospective study by Slentz et al. randomized 196 overweight sedentary adult subjects with dyslipidemia to one of three well‐defined 8‐month treatment groups: aerobic training (AT), resistance training (RT), or combination AT and RT. Visceral and hepatic fat, liver enzymes, and IR improved in the AT groups, compared to only a reduction in subcutaneous fat in the RT group.4 A systematic review and meta‐analysis comparing AT to RT came to similar conclusions.5 In fact, some have shown that the effects of AT on the reduction of hepatic and visceral fat may be independent of weight loss.6 However, the optimal exercise "prescription" has not yet been determined. In this issue of Hepatology, Oh et al. present a retrospective analysis of the effects of varying durations of moderate‐to‐vigorous physical activity (MVPA) over a 12‐week period.8 The data set was comprised of 218 obese middle‐aged Japanese men enrolled in a 12‐week weight reduction program. The presence of hepatic steatosis (HS) was determined with a controlled attenuation parameter using FibroScan. A total of 169 subjects with detectable HS were divided into three groups (<150, 150‐250, and >250 min/wk−1) for 12 weeks. In addition, subjects were given specific dietary guidelines and adherence was assessed by food diary. Patients were stratified according to the quantity of weekly MVPA. The investigators found that only subjects in the highest exercise duration group had favorable changes in metabolic parameters and a significant reduction in hepatic fat content. When compared to those who engaged in <250 min/wk−1 of MVPA, only those that exercised for >250 min/wk−1 had reductions in HS and visceral adipose tissue mass. Whereas beneficial effects of exercise on the liver have previously been reported, these data propose a threshold quantity of exercise that may be necessary for a meaningful improvement in NAFLD. Additionally, the investigators propose mechanisms through which exercise could ameliorate HS and features of the metabolic syndrome by focusing on biological pathways known to be relevant in NAFLD. They compared measures of IR, systemic and hepatic inflammation, plasma lipids, and gene expression from peripheral blood mononuclear cells between the groups. Subjects that engaged in >250 min/wk−1 of MVPA had improved lipid parameters, less IR, reduced markers of oxidative injury, and favorable changes in their adipocytokine profile. However, after accounting for weight loss, the improvement in IR and several adipocytokines was no longer statistically significant. Interestingly, the investigators propose that increased expression of nuclear factor E2‐related factor 2 (Nrf2) may be a mechanism through which vigorous exercise could counteract oxidative stress (OS), known to be important in the pathogenesis of NAFLD and NASH in particular. Nrf2 is a transcription factor regulating the expression of several cytoprotective and antioxidant genes. Thus, it is an important regulator of the antioxidant response against environmental stresses.9 Drugs that target the Nrf2 pathway have been studied in many disorders, with at least one new Nrf2‐activating drug approved by the U.S. Food and Drug Administration. OS is an important contributor to liver injury in NASH. As illustrated by the investigators, high‐intensity exercise can activate Nrf2 and thereby potentially improve our ability to manage OS and attenuate liver injury in the setting of NASH.10 Furthermore, Nrf2 is involved in many pathways relevant to NAFLD and the development of progressive liver injury. In animal models, Nrf2 activation can decrease liver X receptor (LXR)‐dependent hepatic lipogenesis by competing with the farsenoid X receptor, thereby reducing HS.11 Up‐regulation of Nrf2 could conceivably decrease hepatic fibrosis as well by down‐regulation of transforming growth factor beta (TGF‐β).12 Also relevant to NAFLD/NASH, Nrf2 appears to have a role in glucose and bile acid metabolism, though these roles are less well defined.13 Thus, exercise‐induced changes in Nrf2 could explain the beneficial effects of exercise independent of weight loss shown here and by others (Fig. 1).Figure 1: Proposed mechanisms through which exercise could result in reduced liver injury in NASH independent of weight loss via upregulation of Nrf2. Abbreviation: NFKB, nuclear factor kappa B.This is a timely and important article that provides some preliminary evidence for the duration and intensity of exercise needed to reduce HS and other metabolic abnormalities common in NAFLD. Furthermore, these data provide additional evidence that there is more to exercise than the weight loss it induces to support its role in the treatment of NAFLD. However, a critical gap in knowledge still remains as to whether exercise alone without weight loss could ultimately improve liver histological features of NASH, such as ballooning degeneration, lobular inflammation, or fibrosis. Though these findings are intriguing, both the independent effect of exercise on NAFLD as well as its mechanism of action will need to be studied in large, prospective, randomized, controlled trials before we can give our patients the exercise "prescription" most likely to benefit their disease. In the end, the hardest part will be getting them to fill it and take it as directed.