Fibroblast growth factor 21 is required for the therapeutic effects of Lactobacillus rhamnosus GG against fructose-induced fatty liver in mice

Abstract

ObjectivesHigh fructose feeding changes fibroblast growth factor 21 (FGF21) regulation. Lactobacillus rhamnosus GG (LGG) supplementation reduces fructose-induced non-alcoholic fatty liver disease (NAFLD). The aim of this study was to determine the role of FGF21 and underlying mechanisms in the protective effects of LGG.MethodsFGF21 knockout (KO) mice and C57BL/6 wild type (WT) mice were fed 30% fructose for 12 weeks. LGG was administered to the mice in the last 4 weeks during fructose feeding. FGF21-adiponectin (ADPN)-mediated hepatic lipogenesis and inflammation were investigated.ResultsFGF21 expression was robustly increased after 5-weeks of feeding and significantly decreased after 12-weeks of feeding in fructose-induced NAFLD mice. LGG administration reversed the depressed FGF21 expression, increased adipose production of ADPN, and reduced hepatic fat accumulation and inflammation in the WT mice but not in the KO mice. Hepatic nuclear carbohydrate responsive-element binding protein (ChREBP) was increased by fructose and reduced by LGG, resulting in a reduction in the expression of lipogenic genes. The methylated form of protein phosphatase 2A (PP2A) C, which dephosphorylates and activates ChREBP, was upregulated by fructose and normalized by LGG. Leucine carboxyl methyltransferase-1, which methylates PP2AC, was also increased by fructose and decreased by LGG. However, those beneficial effects of LGG were blunted in the KO mice. Hepatic dihydrosphingosine-1-phosphate, which inhibits PP2A, was markedly increased by LGG in the WT mice but attenuated in the KO mice. LGG decreased adipose hypertrophy and increased serum levels of ADPN, which regulates sphingosine metabolism. This beneficial effect was decreased in the KO mice.ConclusionLGG administration increases hepatic FGF21 expression and serum ADPN concentration, resulting in a reduced ChREBP activation through dihydrosphingosine-1-phosphate-mediated PP2A deactivation, and subsequently reversed fructose-induced NAFLD. Thus, our data suggest that FGF21 is required for the beneficial effects of LGG in reversal of fructose-induced NAFLD.

Punicalagin Prevents Hepatic Steatosis through Improving Lipid Homeostasis and Inflammation in Liver and Adipose Tissue and Modulating Gut Microbiota in Western Diet‐Fed Mice

“…[ 6,10 ] Furthermore, numerous studies show that adipokines are required for some therapeutic agents to perform their anti‐NAFLD functions in rodent models. [ 11–14 ] Therefore, regulation of adipokine secretion may serve as a potential therapeutic strategy for NAFLD.…”

Amelioration of Hepatic Steatosis in Mice through Bacteroides uniformis CBA7346-Mediated Regulation of High-Fat Diet-Induced Insulin Resistance and Lipogenesis

“…NAFLD—one of the most prevalent liver diseases in adults—is characterized by an irregular accumulation of triglycerides in hepatocytes [ 1 , 22 ]. Recent studies have reported the administration of probiotics such as Lactobacillus for the treatment and prevention of NAFLD in animal models [ 9 , 23 ]. B. uniformis which is dominant in the human gut, showed anti-obesity effects in mice with HFD-induced obesity [ 13 ].…”

The Speed of Ingestion of a Sugary Beverage Has an Effect on the Acute Metabolic Response to Fructose

“…It is thought that FGF-21 may have a protective role in energy metabolism by acting as an insulin sensitizer [29] and by stimulating the oxidation of fatty acids and inhibition of lipogenesis [30]. Furthermore, FGF-21 was shown to protect against fructose-induced liver inflammation in mice [31]. Nevertheless, elevated circulating FGF-21 levels have been associated with poor metabolic health in humans and shown to correlate positively with fasting glucose [32], fasting insulin, and triglycerides and negatively with high-density lipoprotein cholesterol (HDL) [33].…”