Metformin protects against the development of fructose-induced steatosis in mice: role of the intestinal barrier function

Abstract

To test the hypothesis that metformin protects against fructose-induced steatosis, and if so, to elucidate underlying mechanisms, C57BL/6J mice were either fed 30% fructose solution or plain water for 8 weeks. Some of the animals were concomitantly treated with metformin (300 mg/kg body weight/day) in the drinking solution. While chronic consumption of 30% fructose solution caused a significant increase in hepatic triglyceride accumulation and plasma alanineaminotransferase levels, this effect of fructose was markedly attenuated in fructose-fed mice concomitantly treatment with metformin. The protective effects of the metformin treatment on the onset of fructose-induced non-alcoholic fatty liver disease (NAFLD) were associated with a protection against the loss of the tight junction proteins occludin and zonula occludens 1 in the duodenum of fructose-fed mice and the increased translocation of bacterial endotoxin found in mice only fed with fructose. In line with these findings, in metformin-treated fructose-fed animals, hepatic expression of genes of the toll-like receptor-4-dependent signalling cascade as well as the plasminogen-activator inhibitor/cMet-regulated lipid export were almost at the level of controls. Taken together, these data suggest that metformin not only protects the liver from the onset of fructose-induced NAFLD through mechanisms involving its direct effects on hepatic insulin signalling but rather through altering intestinal permeability and subsequently the endotoxin-dependent activation of hepatic Kupffer cells.

Reactive Oxygen Species-Induced TXNIP Drives Fructose-Mediated Hepatic Inflammation and Lipid Accumulation Through NLRP3 Inflammasome Activation

“…To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars Discussion NAFLD encompasses a spectrum of chronic liver diseases characterized by hepatic inflammation and lipid accumulation. Increased fructose consumption is implicated in the pathogenesis and progression of NAFLD (7,22,24,33,45,(47)(48)(49)59), but the molecular mechanisms involved have not been completely elucidated. Generally, Kupffer cells are the primary source of hepatic inflammatory cytokines such as IL1b.…”

“…Clinical and experimental evidence indicates that excessive fructose consumption is involved in the pathogenesis of metabolic syndrome and associated NAFLD (7,22,24,33,45,(47)(48)(49)59). The direct effect of fructose on hepatic lipid metabolism, which is characterized by intracellular triglyceride (TG) accumulation (hepatic steatosis), is considered the first hit in the pathogenesis of NAFLD.…”

“…The direct effect of fructose on hepatic lipid metabolism, which is characterized by intracellular triglyceride (TG) accumulation (hepatic steatosis), is considered the first hit in the pathogenesis of NAFLD. Hepatocellular oxidative stress as a result of excessive reactive oxygen species (ROS) production due to inflammation or endogenous toxins constitutes the second hit in the pathogenesis of NAFLD and its progression to nonalcoholic steatohepatitis (NASH) (24,(47)(48)(49). However, the molecular mechanisms that underlie fructose-mediated healthy liver/NAFLD/NASH transition are incompletely understood.…”

“…These cytokines are able to induce dyslipidemia and lipid accumulation in hepatocytes (32,54). Moreover, genetic NLRP3 inflammasome deficiency in innate immune cells predisposes animals to develop NAFLD through alterations in gut microbiota (12), and gut-derived endotoxin-dependent activation of Kupffer cells in mice has been suggested to mediate the onset of fructose-induced hepatic steatosis via inducible nitric oxide synthase (iNOS) and Toll-like receptor 4 signaling (47)(48)(49). Lastly, this inflammasome activation in Kupffer cells has been observed in choline-deficient amino-acid-defined (CDAA) diet-induced NASH in mice (30), altogether attesting to the paracrine effects of immune cell-mediated inflammasome activation and inflammatory signaling on hepaocellular lipid metabolism.…”

Extrahepatic Diseases and NAFLD: The Triangular Relationship between NAFLD, Type 2-Diabetes and Dysbiosis

“…In addition, a study has shown that metformin protects against fructose-induced steatosis [45] . Spruss et al [47] found that in mice with NAFLD, metformin reduces the translocation of gut bacteria and bacterial endotoxins, by protecting mice from the fructose-induced loss of tight junction proteins and zonula occludens 1 ( fig. 2 ) [46] .…”