Liver and Metformin: Lessons of a fructose diet in mice

Abstract

Studies show that the continuous consumption of fructose can lead to nonalcoholic fatty liver disease (NAFLD) and steatohepatitis. We aimed to investigate the role of Metformin in an animal model of liver injury caused by fructose intake, focusing on the molecular markers of lipogenesis, beta-oxidation, and antioxidant defenses. Male three months old C57BL/6 mice were divided into control group (C) and fructose group (F, 47% fructose), maintained for ten weeks. After, the groups received Metformin or vehicle for a further eight weeks: control (C), control + Metformin (CM), fructose (F), and fructose + Metformin (FM). Fructose resulted in hepatic steatosis, insulin resistance and lower insulin sensitivity in association with higher mRNA levels of proteins linked with de novo lipogenesis and increased lipid peroxidation. Fructose diminished mRNA expression of antioxidant enzymes, and of proteins responsible for mitochondrial biogenesis. Metformin reduced de novo lipogenesis and increased the expression of proteins related to mitochondrial biogenesis, thereby increasing beta-oxidation and decreasing lipid peroxidation. Also, Metformin upregulated the expression and activity of antioxidant enzymes, providing a defense against increased reactive oxygen species generation. Therefore, a significant reduction in triglyceride accumulation in the liver, steatosis and lipid peroxidation was observed in the FM group. In conclusion, fructose increases de novo lipogenesis, reduces the antioxidant defenses, and diminishes mitochondrial biogenesis. After an extended period of fructose intake, Metformin treatment, even in continuing the fructose intake, can reverse, at least partially, the liver injury and prevents NAFLD progression to more severe states.

<p>Lycopene Improves the Metformin Effects on Glycemic Control and Decreases Biomarkers of Glycoxidative Stress in Diabetic Rats</p>

“… 44 The levels of biomarkers related to oxidative damage were also decreased in liver and kidneys of diabetic rats treated with metformin, as previously observed by others. 45 , 46 However, different from lycopene, metformin alone did not improve the activity of SOD in these tissues, only caused increases in the activity of CAT. It can be inferred that the improvement in the activity of CAT was sufficient to mitigate the oxidative stress in tissues of diabetic rats treated with metformin.…”

Of mice and men: Is there a future for metformin in the treatment of hepatic steatosis?

“…For example, metformin is reported to decrease SREBP‐1c expression, one of the master regulators of the DNL pathway, in HFD‐fed mice . Additionally, in fructose‐fed mice, metformin treatment decreased the expression of the transcriptional regulators of DNL, and IHTAG content . ACC1 inhibition by AMPK seems to be critical to this effect; when ACC1 is rendered constitutively active (and cannot be inhibited by AMPK), mice spontaneously develop steatosis which cannot be reversed by treatment with metformin.…”

Metformin induces lipogenic differentiation in myofibroblasts to reverse mouse and human lung fibrosis

“…Therefore, its role in homeostasis and disease is strictly context-dependent. Interestingly, it has been reported that metformin inhibits the upregulation of PPARg and PLIN2 in mouse hepatocytes in response to fructose diet 38 . Metformin, however, does not alter PPARg and PLIN2 expression levels in animals that receive normal diet 38 .…”

“…Interestingly, it has been reported that metformin inhibits the upregulation of PPARg and PLIN2 in mouse hepatocytes in response to fructose diet 38 . Metformin, however, does not alter PPARg and PLIN2 expression levels in animals that receive normal diet 38 . Moreover, it has been shown that metformin inhibits adipogenesis in mesenchymal stem cells 39 and embryonic mouse preadipocyte cell line 3T3-L1 40 .…”