Sucralose, a Non-nutritive Artificial Sweetener Exacerbates High Fat Diet-Induced Hepatic Steatosis Through Taste Receptor Type 1 Member 3

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease globally, and it is strongly associated with obesity. To combat obesity, artificial sweeteners are often used to replace natural sugars, and sucralose is one of the most extensively used sweeteners. It was known that sucralose exerted effects on lipid metabolism dysregulation, and hepatic inflammation; however, the effects of sucralose on hepatic steatosis were still obscure. In this study, we found that supplements of sucralose enhanced high-fat-diet (HFD)-induced hepatic steatosis. In addition, treatment of sucralose increased reactive oxygen species (ROS) generation and induced endoplasmic reticulum (ER) stress in HepG2 cells. Pretreatment of ROS or ER stress inhibitors reversed the effects of sucralose on lipogenesis. Furthermore, pretreatment of taste receptor type 1 membrane 3 (T1R3) inhibitor or T1R3 knockdown reversed sucralose-induced lipogenesis in HepG2 cells. Taken together, sucralose might activate T1R3 to generate ROS and promote ER stress and lipogenesis, and further accelerate to the development of hepatic steatosis.

Newborns from Mothers Who Intensely Consumed Sucralose during Pregnancy Are Heavier and Exhibit Markers of Metabolic Alteration and Low-Grade Systemic Inflammation: A Cross-Sectional, Prospective Study

“…In this sense, sucralose increases the expression of fatty acid synthase (FAS) and fatty acid-binding protein 4 (FABP4) on the in vitro cultured 3T3L1 adipocytes and adipose tissue of mouse offspring born to sucralose-fed dams [ 13 ]. Likewise, recent evidence shows that sucralose feeding enhances FAS expression in the liver of mice with HFD-induced steatosis via the taste receptor type 1 member 3 (T1R3), a member of the sucralose’s receptor family mediating sweet taste perception [ 25 , 26 ]. Taking this information together, it is feasible that sucralose of maternal origin may directly promote lipogenesis and fat mass expansion in the offspring via T1R3; thus, partially explaining the weight gain observed in neonates exposed to this NNS during gestation.…”

Sucralose: From Sweet Success to Metabolic Controversies—Unraveling the Global Health Implications of a Pervasive Non-Caloric Artificial Sweetener

“…These data are intriguing because in vitro cultures of HepG2 cells show a decrease in the levels of the hypogenic transcription factor when the T1R3 receptor is blocked, compared to cells cultured in the presence of sucralose and the T1R3 receptor [ 71 ].…”

“…This indicates that the binding of sucralose to the T1R3 receptor can enhance lipogenic activity in the liver. Furthermore, sucralose has been demonstrated to induce ROS production in the liver through T1R3, thereby facilitating hepatic lipogenesis and contributing to HFD-induced fatty liver [ 71 ]. Alyaa F. et al validated these findings in mice fed with sucralose [ 69 ].…”

Is the Use of Artificial Sweeteners Beneficial for Patients with Diabetes Mellitus? The Advantages and Disadvantages of Artificial Sweeteners

“…Sucralose also enhanced high-fat-diet (HFD)-induced hepatic steatosis [ 40 ]. In addition, treatment with sucralose increased reactive oxygen species (ROS) generation and induced endoplasmic reticulum (ER) stress in HepG2 cells.…”