Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease with no therapeutic consensus. Oxidation and inflammation are hallmarks in the progression of this complex disease, which also involves interactions between the genetic background and the environment. Mastiha is a natural nutritional supplement known to possess antioxidant and anti-inflammatory properties. This study investigated how a 6-month Mastiha supplementation (2.1 g/day) could impact the antioxidant and inflammatory status of patients with NAFLD, and whether genetic variants significantly mediate these effects. We recruited 98 patients with obesity (BMI ≥ 30 kg/m2) and NAFLD and randomly allocated them to either the Mastiha or the placebo group for 6 months. The anti-oxidative and inflammatory status was assessed at baseline and post-treatment. Genome-wide genetic data was also obtained from all participants, to investigate gene-by-Mastiha interactions. NAFLD patients with severe obesity (BMI > 35kg/m2) taking the Mastiha had significantly higher total antioxidant status (TAS) compared to the corresponding placebo group (P value=0.008). We did not observe any other significant change in the investigated biomarkers as a result of Mastiha supplementation alone. We identified several novel gene-by-Mastiha interaction associations with levels of cytokines and antioxidant biomarkers. Some of the identified genetic loci are implicated in the pathological pathways of NAFLD, including the lanosterol synthase gene (LSS) associated with glutathione peroxidase activity (Gpx) levels, the mitochondrial pyruvate carrier-1 gene (MPC1) and the sphingolipid transporter-1 gene (SPNS1) associated with hemoglobin levels, the transforming growth factor‐beta‐induced gene (TGFBI) and the micro-RNA 129-1 (MIR129-1) associated with IL-6 and the granzyme B gene (GZMB) associated with IL-10 levels. Within the MAST4HEALTH randomized clinical trial (NCT03135873, www.clinicaltrials.gov) Mastiha supplementation improved the TAS levels among NAFLD patients with severe obesity. We identified several novel genome-wide significant nutrigenetic interactions, influencing the antioxidant and inflammatory status in NAFLD.Clinical Trial Registration ClinicalTrials.gov, identifier NCT03135873.
Highlights
non-alcoholic fatty liver disease (NAFLD) is one of the major causes of liver dysfunction worldwide and the most common liver disease in Western populations, characterized by hepatic fat accumulation of more than 5% [1, 2]
As in our previous analyses [23], we stratified our individuals by body mass index (BMI) category and the baseline characteristics per trial group are presented in Table 2, while the baseline characteristics for all individuals stratified only by BMI category are presented in Supplementary Table 2
We found a significant increase in total antioxidant status (TAS) within the Mastiha group post-treatment compared to the placebo group, albeit only in the BMI>35kg/m2 group (n=28) (Supplementary Table 3 and Figure 1)
Summary
NAFLD is one of the major causes of liver dysfunction worldwide and the most common liver disease in Western populations, characterized by hepatic fat accumulation of more than 5% [1, 2]. The condition encompasses a wide spectrum of disorders, starting from mild hepatic fat deposition to more progressive steatosis, accompanied by fibrosis and cirrhosis and progressively resulting in hepatocellular carcinoma [1, 2]. The pathogenesis of NAFLD is not fully elucidated but according to the “multiple parallel hits hypothesis” model, hepatic accumulation of triglycerides triggers multiple conditions in the liver. These contribute synergistically to disease onset and progression, including increased hepatic oxidative stress linked to progressive cell death [3]. There is growing evidence that inflammatory markers and oxidative stress play a pivotal role in the pathophysiology of the disease, highlighting their role as potential therapeutic targets [3, 5,6,7]
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