Kefir peptides prevent high-fructose corn syrup-induced non-alcoholic fatty liver disease in a murine model by modulation of inflammation and the JAK2 signaling pathway

Abstract

Objective:In recent years, people have changed their eating habits, and high-fructose-containing bubble tea has become very popular. High-fructose intake has been suggested to be a key factor that induces non-alcoholic fatty liver disease (NAFLD). Kefir, a fermented milk product composed of microbial symbionts, has demonstrated numerous biological activities, including antibacterial, antioxidant and immunostimulating effects. The present study aims to evaluate the effects of kefir peptides on high-fructose-induced hepatic steatosis and the possible molecular mechanism.Results:An animal model of 30% high-fructose-induced NAFLD in C57BL/6J mice was established. The experiment is divided into the following six groups: (1) normal: H2O drinking water; (2) mock: H2O+30% fructose; (3) KL: low-dose kefir peptides (50 mg kg−1)+30% fructose; (4) KM: medium-dose kefir peptides (100 mg kg−1)+30% fructose; (5) KH: high-dose kefir peptides (150 mg kg−1)+30% fructose; and (6) CFM: commercial fermented milk (100 mg kg−1)+30% fructose. The results show that kefir peptides improve fatty liver syndrome by decreasing body weight, serum alanine aminotransferase, triglycerides, insulin and hepatic triglycerides, cholesterol, and free fatty acids as well as the inflammatory cytokines (TNF-α, IL-6 and IL-1β) that had been elevated in fructose-induced NAFLD mice. In addition, kefir peptides markedly increased phosphorylation of AMPK to downregulate its targeted enzymes, ACC (acetyl-CoA carboxylase) and SREBP-1c (sterol regulatory element-binding protein 1), and inhibited de novo lipogenesis. Furthermore, kefir peptides activated JAK2 to stimulate STAT3 phosphorylation, which can translocate to the nucleus, and upregulated several genes, including the CPT1 (carnitine palmitoyltransferase-1) involved in fatty acid oxidation.Conclusion:Our data have demonstrated that kefir peptides can improve the symptoms of NAFLD, including body weight, energy intake, inflammatory reaction and the formation of fatty liver by activating JAK2 signal transduction through the JAK2/STAT3 and JAK2/AMPK pathways in the high-fructose-induced fatty liver animal model. Therefore, kefir peptides may have the potential for clinical application for the prevention or treatment of clinical metabolic syndrome.

Modulation of hepatic inflammation and energy-sensing pathways in the rat liver by high-fructose diet and chronic stress

“…In our study, high-fructose diet diminished hepatic AMPK activity, represented as decreased phospho-AMPK/AMPK ratio [55]. In agreement with the results obtained by Chen et al [56], high-fructose diet increased total AMPK level without significantly affecting phospho-AMPK. Several mechanisms could account for the observed effects of fructose diet on the AMPK activity.…”

“…It is conceivable that fructoseinduced hepatic inflammation through the stimulation of the NFκB signaling pathway is facilitated by decreased AMPK activity, as observed in the fructose-fed group [16]. This hypothesis is supported by prior findings that consumption of 30% fructose solution leads concomitantly to increased pro-inflammatory cytokines and decreased phospho-AMPK/ AMPK ratio in the rat liver [56] and that fructose-induced inflammation and NFκB activation in the diabetic murine heart is causally related to reduced AMPK activity [12]. The suggested role of AMPK as an important energy sensor linking fructose metabolism to the regulation of inflammatory signaling is further supported by recent findings of Cao et al [60], showing that fructose amplifies inflammatory potential in human monocytic cells via a reduction of AMPK activity.…”

The Many Faces of Kefir Fermented Dairy Products: Quality Characteristics, Flavour Chemistry, Nutritional Value, Health Benefits, and Safety

“…The soluble non-bacterial fraction of kefir decreased lipid deposition independent of hypercholesterolemia in LDLr-/-mice [92], likely attributed to kefir peptides content found effective to improve body weight, energy intake, and protection against fatty liver [98]. Peptides derived from the microbial fermentation of milk protein account for many fermented dairy products' reported health benefits and are likely to be same in the case of kefir.…”

PPARα-independent action against metabolic syndrome development by fibrates is mediated by inhibition of STAT3 signalling

“…In mice fed high‐fat diet, the STAT3 signalling inhibition by lycopene attenuated development of lipid accumulation, inflammation, insulin resistance and metabolic dysfunction . In C57BL/6J mice treated with 30% fructose, when the JAK2/STAT3 was activated, the symptoms of NAFLD were improved . In another mouse model treated with lipopolysaccharide, inhibiting STAT3 pathway led to alleviation of adipocyte inflammation .…”

“…[13] In C57BL/6J mice treated with 30% fructose, when the JAK2/STAT3 was activated, the symptoms of NAFLD were improved. [14] In another mouse model treated with lipopolysaccharide, inhibiting STAT3 pathway led to alleviation of adipocyte inflammation. [15] These reports suggested that MS symptoms were associated with typical inflammation pathways NF-jB, JNK and STAT3.…”