Effects of Calorie Restricted Diet on Oxidative/Antioxidative Status Biomarkers and Serum Fibroblast Growth Factor 21 Levels in Nonalcoholic Fatty Liver Disease Patients: A Randomized, Controlled Clinical Trial

Abstract

Oxidative stress plays a fundamental role in the development and progression of nonalcoholic fatty liver disease (NAFLD). This study aimed to investigate the effects of a calorie-restricted (CR) diet on oxidative/anti-oxidative status in patients with NAFLD and the potential mediating role of fibroblast growth factor 21 (FGF-21) in this regard. This randomized, controlled clinical trial was carried out on sixty patients with NAFLD aged 20 to 60 years with body mass index (BMI) ranging from 25 to 35 kg/m2. Participants were randomly assigned to either the CR diet group (received a prescribed low-calorie diet for twelve weeks, n = 30) or the control group (n = 30). Fasting blood samples, anthropometric measurements, dietary intake, and physical activity data were collected for all participants at baseline and at the end of the trial. Significant reductions in weight, BMI, waist circumference, and serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were observed in the CR diet group compared to the control group (all p< 0.05). Liver steatosis grade, serum levels of malondialdehyde (MDA), total antioxidant capacity (TAC), and FGF-21, as well as erythrocyte superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities did not show significant changes in the CR group when compared to the controls at the end of the study (p > 0.05). CR diet with moderate weight loss has some favorable effects on NAFLD but was not able to modify oxidative/anti-oxidative status in these patients. Future studies are warranted to target the effects of long-term interventions with a greater weight loss in this patient population.

Plasma FGF21 Levels Are Not Associated with Weight Loss or Improvements in Metabolic Health Markers upon 12 Weeks of Energy Restriction: Secondary Analysis of an RCT

“…Despite substantial weight loss of 7.3 kg on average and concomitant health improvements [ 32 ], 12 weeks of 25% energy reduction did not affect fasting FGF21 levels. Previous weight loss trials have reported conflicting findings, with some trials reporting a reduction in fasting FGF21 levels upon diet-induced weight loss [ 9 , 10 , 11 , 12 , 13 ], and others reporting an increase [ 40 ] or no effect on circulating FGF21 levels [ 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Generally, the studies that report a change in plasma fasting FGF21 were performed in individuals with more severely impaired metabolic health (e.g., T2DM, NAFLD, morbid obesity), who typically have elevated FGF21 levels and thus more room for improvement compared to individuals in this study.…”

“…Accordingly, circulating FGF21 levels have been reported to positively associate with BMI, body fat, liver fat content, blood pressure, insulin resistance (IR) and atherogenic lipid profiles [ 5 , 6 ], as well as predict incident metabolic syndrome and T2DM [ 7 , 8 ]. It is unclear whether and how weight loss and accompanying health improvements affect FGF21 levels, with some trials reporting reduced levels of circulating FGF21 upon diet-induced weight loss [ 9 , 10 , 11 , 12 , 13 ], and others reporting no effects on FGF21 [ 14 , 15 , 16 , 17 , 18 , 19 , 20 ].…”

Fibroblast Growth Factor-21 as a Potential Therapeutic Target of Nonalcoholic Fatty Liver Disease

“… 70 On the contrary, an open-label randomized controlled trial (RCT) in overweight/obese individuals with NAFLD reported no effect of a calorie-restricted diet or a common (characterized as “healthy”) diet on both circulating FGF-21 and NAFLD. 74 These results warrant further research to definitely show whether the beneficial effect of lifestyle modifications on NAFLD 75 may be partly mediated by FGF-21, as well as whether there are distinct effects in different ages.…”

“… Change in circulating FGF-21 was positively associated with change in HFC. Asghari (2022) 74 Open-label RCT Overweight/obese with US-defined NAFLD (30) Overweight/obese with US-defined NAFLD (30) Calorie-restricted diet vs “healthy” diet 12 weeks No Effect of calorie- restricted diet on circulating FGF-21 and NAFLD. Circulating FGF-21 and hepatic steatosis remained unaffected after either diet.…”

Effects of various interventions on non-alcoholic fatty liver disease (NAFLD): A systematic review and network meta-analysis

“…Among them, 253 studies were excluded, including 51 studies in which the control group received other drugs, 16 studies which were non-RCTs, 13 studies in which no indicators were related to NAFLD, 79 studies in which the control group had other liver diseases, 74 studies which were reviews, and 20 studies which had incomplete data. In the end, 43 studies ( Pugh et al, 2013 ; Pugh et al, 2014 ; Abenavoli et al, 2015 ; Hallsworth et al, 2015 ; Dong et al, 2016 ; Panahi et al, 2016 ; Rahmani et al, 2016 ; Zhang et al, 2016 ; Abenavoli et al, 2017 ; Cheng et al, 2017 ; Houghton et al, 2017 ; Manzhalii et al, 2017 ; Misciagna et al, 2017 ; Navekar et al, 2017 ; Panahi et al, 2017 ; Dinu et al, 2018 ; Katsagoni et al, 2018 ; Wong et al, 2018 ; Ahn et al, 2019 ; Cai et al, 2019 ; Chashmniam et al, 2019 ; Ghaffari et al, 2019 ; Ghetti et al, 2019 ; Mirhafez et al, 2019 ; Saadati et al, 2019 ; Campanella et al, 2020 ; Cicero et al, 2020 ; Hariri et al, 2020 ; Nourian et al, 2020 ; Saberi-Karimian et al, 2020 ; Çevik Saldiran et al, 2020 ; Chong et al, 2021 ; Mirhafez et al, 2021 ; Mohamad Nor et al, 2021 ; Alami et al, 2022 ; Asghari et al, 2022 ; Chiurazzi et al, 2022 ; George et al, 2022 ; Khodami et al, 2022 ; Li et al, 2022 ; Mobasheri et al, 2022 ; Yurtdaş et al, 2022 ; Ezpeleta et al, 2023 ) were included in the NMA. The selection process is shown in Figure 1 .…”