Rebaudioside affords hepatoprotection ameliorating sugar sweetened beverage- induced nonalcoholic steatohepatitis

Abstract

Sugar-sweetened beverage consumption is a known independent risk factor for nonalcoholic steatohepatitis (NASH). Non-caloric sweeteners (NCS) are food additives providing sweetness without calories and are considered safe and/or not metabolized by the liver. The potential role of newer NCS in the regulation of NASH, however, remain unknown. Our study aimed to determine the impact of newer NCS including Rebaudioside A and sucralose on NASH using high fat diet induced obesity mouse model by substituting fructose and sucrose with NCS in the drinking water. We characterized the phenotype of NCS-treated obesity and investigated the alterations of hepatic function and underlying mechanisms. We found that NCS have no impact on weight gain and energy balance in high fat diet induced obesity. However, in comparison to fructose and sucrose, Rebaudioside A significantly improved liver enzymes, hepatic steatosis and hepatic fibrosis. Additionally, Rebaudioside A improved endoplasmic reticulum (ER) stress related gene expressions, fasting glucose levels, insulin sensitivity and restored pancreatic islet cell mass, neuronal innervation and microbiome composition. We concluded that Rebaudioside A significantly ameliorated murine NASH, while the underlying mechanisms requires further investigation. Current treatment strategies for nonalcoholic steatohepatitis (NASH) have focused on lifestyle management of modifiable risk factors, through a combination of diet and exercise 1-3. Potential therapeutic targets for NASH intersect with the complex pathogenesis of NASH including hepatic steatosis from the imbalance of lipogenesis and free fatty acid (FFA) promoting inflammatory response and fibrosis progression 4,5. However, despite pharmaceutical agents currently in advanced stages of clinical testing 6-8 , NASH is on track predicted to become the main reason for liver transplant in the very near future 9. Therefore, it is essential to continue to explore novel NASH therapies. Sugar sweetened beverages are now well acknowledged to have severe consequences on human health. Consequently, non-caloric sweeteners (NCS) such as aspartame, sucralose, saccharin, and Rebaudioside A have increased in popularity and usage. However, there is a limited evidence for the benefits of frequent consumption of NCS sugar substitutes. This is especially true for the most recent addition Rebaudioside A, that is an extract of the stevia leaf that provides sweetness without calories 10. Interestingly, recent literature has reported that Rebaudioside A may in fact play a role in glucose metabolism and has even been reported to improve post-prandial glucose-insulin index 11 , and its consumption may result in weight loss in mice fed a high fat diet 12. These observations suggest a potential role for Rebaudioside A on glucose metabolism in general, and on liver function and NASH in particular. The well-known interactions between human health, diet and intestinal microbiota are based on the involvement of the microbiome in metabolism and immunity, which also par...

The sensory properties and metabolic impact of natural and synthetic sweeteners

“…Thus, in a population that exhibits gut dysbiosis (i.e., obese or diabetic populations), a beneficial metabolic effect of Reb A consumption may be observed. A recent study in mice found that Reb A offers protection against nonalcoholic fatty liver disease (Xi et al., 2020). Reb A consumption was associated with significantly improved liver enzymes, hepatic steatosis, fasting glucose levels, insulin sensitivity, and restored microbiome composition with diet‐induced obesity.…”

Steviol Glycoside, L-Arginine, and Chromium(III) Supplementation Attenuates Abnormalities in Glucose Metabolism in Streptozotocin-Induced Mildly Diabetic Rats Fed a High-Fat Diet

“…In summary, in most cases, supplementation with ST mixed with high doses of L-arginine or Cr(III) was found to be most effective in alleviating hepatic, pancreatic, and renal abnormalities in diabetic animals. Such an impact on the liver, pancreas or kidneys was reported in many previous studies, which can be explained by the overall protecting property of Stevia rebaudiana leaves and/or its isolated compounds [ 28 , 60 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 96 , 97 , 98 , 99 , 100 ], L-arg [ 78 , 79 , 91 , 92 , 101 , 102 ] and Cr(III) [ 58 , 80 , 81 , 82 , 94 , 95 , 103 , 104 ].…”

Comparative Effects of Whole Stevia Leaf and Rebaudioside A on Oxidative Stress in Male Obese Sprague Dawley Rats

“…Our result was also affirmed by Dong et al in 2020. 21 They also concluded that oxidative stress and inflammatory response are ameliorated by giving Rebaudioside A in vitro study. Further it was reported that Rebaudioside protected human hepatocytes from oxidative stress induced by CCL4 in culture.…”