Are BPA Substitutes as Obesogenic as BPA?

Metabolic diseases, such as obesity, Type II diabetes and hepatic steatosis, are a significant public health concern affecting more than half a billion people worldwide. The prevalence of these diseases is constantly increasing in developed countries, affecting all age groups. The pathogenesis of metabolic diseases is complex and multifactorial. Inducer factors can either be genetic or linked to a sedentary lifestyle and/or consumption of high-fat and sugar diets. In 2002, a new concept of "environmental obesogens" emerged, suggesting that environmental chemicals could play an active role in the etiology of obesity. Bisphenol A (BPA), a xenoestrogen widely used in the plastic food packaging industry has been shown to affect many physiological functions and has been linked to reproductive, endocrine and metabolic disorders and cancer. Therefore, the widespread use of BPA during the last 30 years could have contributed to the increased incidence of metabolic diseases. BPA was banned in baby bottles in Canada in 2008 and in all food-oriented packaging in France from 1 January 2015. Since the BPA ban, substitutes with a similar structure and properties have been used by industrials even though their toxic potential is unknown. Bisphenol S has mainly replaced BPA in consumer products as reflected by the almost ubiquitous human exposure to this contaminant. This review focuses on the metabolic effects and targets of BPA and recent data, which suggest comparable effects of the structural analogs used as substitutes.

Activation of the Constitutive Androstane Receptor induces hepatic lipogenesis and regulates Pnpla3 gene expression in a LXR-independent way.

The Constitutive Androstane Receptor (CAR, NR1I3) has been newly described as a regulator of energy metabolism. A relevant number of studies using animal models of obesity suggest that CAR activation could be beneficial on the metabolic balance. However, this remains controversial and the underlying mechanisms are still unknown. This work aimed to investigate the effect of CAR activation on hepatic energy metabolism during physiological conditions, i.e. in mouse models not subjected to metabolic/nutritional stress. Gene expression profiling in the liver of CAR knockout and control mice on chow diet and treated with a CAR agonist highlighted CAR-mediated up-regulations of lipogenic genes, concomitant with neutral lipid accumulation. A strong CAR-mediated up-regulation of the patatin-like phospholipase domain-containing protein 3 (Pnpla3) was demonstrated. Pnpla3 is a gene whose polymorphism is associated with the pathogenesis of nonalcoholic fatty liver disease (NAFLD) development. This observation was confirmed in human hepatocytes treated with the antiepileptic drug and CAR activator, phenobarbital and in immortalized human hepatocytes treated with CITCO. Studying the molecular mechanisms controlling Pnpla3 gene expression, we demonstrated that CAR does not act by a direct regulation of Pnpla3 transcription or via the Liver X Receptor but may rather involve the transcription factor Carbohydrate Responsive Element-binding protein. These data provide new insights into the regulation by CAR of glycolytic and lipogenic genes and on pathogenesis of steatosis. This also raises the question concerning the impact of drugs and environmental contaminants in lipid-associated metabolic diseases.

Hepatic Fasting-Induced PPARα Activity Does Not Depend on Essential Fatty Acids.

The liver plays a central role in the regulation of fatty acid metabolism, which is highly sensitive to transcriptional responses to nutrients and hormones. Transcription factors involved in this process include nuclear hormone receptors. One such receptor, PPARα, which is highly expressed in the liver and activated by a variety of fatty acids, is a critical regulator of hepatic fatty acid catabolism during fasting. The present study compared the influence of dietary fatty acids and fasting on hepatic PPARα-dependent responses. Pparα(-/-) male mice and their wild-type controls were fed diets containing different fatty acids for 10 weeks prior to being subjected to fasting or normal feeding. In line with the role of PPARα in sensing dietary fatty acids, changes in chronic dietary fat consumption influenced liver damage during fasting. The changes were particularly marked in mice fed diets lacking essential fatty acids. However, fasting, rather than specific dietary fatty acids, induced acute PPARα activity in the liver. Taken together, the data imply that the potent signalling involved in triggering PPARα activity during fasting does not rely on essential fatty acid-derived ligand.

Essential fatty acids deficiency promotes lipogenic gene expression and hepatic steatosis through the liver X receptor.

BACKGROUND & AIMS: Nutrients influence non-alcoholic fatty liver disease. Essential fatty acids deficiency promotes various syndromes, including hepatic steatosis, through increased de novo lipogenesis. The mechanisms underlying such increased lipogenic response remain unidentified. METHODS: We used wild type mice and mice lacking Liver X Receptors to perform a nutrigenomic study that aimed at examining the role of these transcription factors. RESULTS: We showed that, in the absence of Liver X Receptors, essential fatty acids deficiency does not promote steatosis. Consistent with this, Liver X Receptors are required for the elevated expression of genes involved in lipogenesis in response to essential fatty acids deficiency. CONCLUSIONS: This work identifies, for the first time, the central role of Liver X Receptors in steatosis induced by essential fatty acids deficiency.

Low doses of bisphenol A induce gene expression related to lipid synthesis and trigger triglyceride accumulation in adult mouse liver.

UNLABELLED: Changes in lifestyle are suspected to have strongly influenced the current obesity epidemic. Based on recent experimental, clinical, and epidemiological work, it has been proposed that some food contaminants may exert damaging effects on endocrine and metabolic functions, thereby promoting obesity and associated metabolic diseases such as nonalcoholic fatty liver disease (NAFLD). In this work, we investigated the effect of one suspicious food contaminant, bisphenol A (BPA), in vivo. We used a transcriptomic approach in male CD1 mice exposed for 28 days to different doses of BPA (0, 5, 50, 500, and 5,000 µg/kg/day) through food contamination. Data analysis revealed a specific impact of low doses of BPA on the hepatic transcriptome, more particularly on genes involved in lipid synthesis. Strikingly, the effect of BPA on the expression of de novo lipogenesis followed a nonmonotonic dose-response curve, with more important effects at lower doses than at the higher dose. In addition to lipogenic enzymes (Acc, Fasn, Scd1), the expression of transcription factors such as liver X Receptor, the sterol regulatory element binding protein-1c, and the carbohydrate responsive element binding protein that govern the expression of lipogenic genes also followed a nonmonotonic dose-response curve in response to BPA. Consistent with an increased fatty acid biosynthesis, determination of fat in the liver showed an accumulation of cholesteryl esters and of triglycerides. CONCLUSION: Our work suggests that exposure to low BPA doses may influence de novo fatty acid synthesis through increased expression of lipogenic genes, thereby contributing to hepatic steatosis. Exposure to such contaminants should be carefully examined in the etiology of metabolic diseases such as NAFLD and nonalcoholic steatohepatitis.

Dietary oleic acid regulates hepatic lipogenesis through a liver X receptor-dependent signaling.

Olive oil consumption is beneficial for health as it is associated with a decreased prevalence of cancer and cardiovascular diseases. Oleic acid is, by far, the most abundant component of olive oil. Since it can be made through de novo synthesis in animals, it is not an essential fatty acid. While it has become clear that dietary oleic acid regulates many biological processes, the signaling pathway involved in these regulations remains poorly defined. In this work we tested the impact of an oleic acid-rich diet on hepatic gene expression. We were particularly interested in addressing the contribution of Liver X Receptors (LXR) in the control of genes involved in hepatic lipogenesis, an essential process in whole body energy homeostasis. We used wild-type mice and transgenic mice deficient for both α and ß Liver X Receptor isoforms (LXR-/-) fed a control or an oleate enriched diet. We observed that hepatic-lipid accumulation was enhanced as well as the expression of lipogenic genes in the liver of wild-type mice fed the oleate enriched diet. In contrast, none of these changes occurred in the liver of LXR-/- mice. Strikingly, oleate-rich diet reduced cholesterolemia in wild-type mice and induced signs of liver inflammation and damage in LXR-/- mice but not in wild-type mice. This work suggests that dietary oleic acid reduces cholesterolemia while promoting LXR-dependent hepatic lipogenesis without detrimental effects to the liver.

Sorcin Links Pancreatic ß-Cell Lipotoxicity to ER Ca2+ Stores.

Preserving ß-cell function during the development of obesity and insulin resistance would limit the worldwide epidemic of type 2 diabetes. Endoplasmic reticulum (ER) calcium (Ca(2+)) depletion induced by saturated free fatty acids and cytokines causes ß-cell ER stress and apoptosis, but the molecular mechanisms behind these phenomena are still poorly understood. Here, we demonstrate that palmitate-induced sorcin downregulation and subsequent increases in glucose-6-phosphatase catalytic subunit-2 (G6PC2) levels contribute to lipotoxicity. Sorcin is a calcium sensor protein involved in maintaining ER Ca(2+) by inhibiting ryanodine receptor activity and playing a role in terminating Ca(2+)-induced Ca(2+) release. G6PC2, a genome-wide association study gene associated with fasting blood glucose, is a negative regulator of glucose-stimulated insulin secretion (GSIS). High-fat feeding in mice and chronic exposure of human islets to palmitate decreases endogenous sorcin expression while levels of G6PC2 mRNA increase. Sorcin-null mice are glucose intolerant, with markedly impaired GSIS and increased expression of G6pc2 Under high-fat diet, mice overexpressing sorcin in the ß-cell display improved glucose tolerance, fasting blood glucose, and GSIS, whereas G6PC2 levels are decreased and cytosolic and ER Ca(2+) are increased in transgenic islets. Sorcin may thus provide a target for intervention in type 2 diabetes.

Adverse effects of long-term exposure to bisphenol A during adulthood leading to hyperglycaemia and hypercholesterolemia in mice.

Bisphenol A (BPA) is a suspected endocrine disruptor highly prevalent in our environment since it is used as monomer of polycarbonate plastics and epoxy resins. Recent epidemiological and animal studies have suggested that BPA exposure may influence the development of obesity and related pathologies such as type 2 diabetes, and cardiovascular diseases. However, experimental studies have often focused on short-term exposures. In this study, we investigated the effect of several months of BPA exposure on hepatic and plasma metabolic markers in adult mice. Male CD1 mice were exposed during 8 months to five different BPA doses below or equivalent to the current no observed adverse effect level (NOAEL: 5000 µg/kg/day) through drinking water. Plasma lipid profiles and liver transcriptomic analysis were performed in control and BPA-treated animals. We report a specific impact of BPA exposure on glycaemia, glucose tolerance and cholesterolemia. Consistent with the hypercholesterolemia in BPA-treated animals, RT-qPCR performed on hepatic mRNA from same animals demonstrated an overexpression of key genes involved in cholesterol biosynthesis, namely, Mvd, Lss Hmgcr, and Sqle. BPA also induced the expression of the sterol regulatory element-binding proteins 2, a master regulator of hepatic cholesterol biosynthesis. As shown by the plasma lathosterol to cholesterol ratio, a surrogate marker for cholesterol biosynthesis, whole body cholesterol de novo synthesis was also increased in BPA-exposed animals. These original results are consistent with many epidemiological studies reporting on a link between BPA exposure and the onset of cardiovascular diseases.