• 2019-07
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  • As depicted above numerous parallels can


    As depicted above, numerous parallels can be drawn between the mechanisms regulating cortisol metabolism in the adrenal and bile Solasodine metabolism in the liver. Besides, bile acids may also have effects on the central nervous system (CNS) and on the regulation of the HPA axis (Fig. 2). Bile duct-ligated rats show a suppressed secretion of CRH and their stress response is impaired as reflected by an inadequate rise of ACTH and corticosterone levels [59]. The apical sodium-bile acid transporter ASBT was implicated in central nervous uptake of bile acids leading to activation of the glucocorticoid receptor GR in the hypothalamus finally repressing CRH transcription und secretion in bile duct-ligated rats [60]. In addition, TGR5 is expressed in the CNS both in astrocytes and neurons of rodents and humans [61] and TGR5 mRNA was detected in the hypothalamus and in the pituitary gland in mice [62]. In summary, these findings provide the basis for the assumption that cholestatic liver diseases with elevated bile acid levels might impact on adrenal function.
    Assessment of adrenal function
    Relative adrenal insufficiency and its diagnosis in liver disease
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    Introduction Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as the liver component of metabolic syndrome. According to recent data, it is estimated that approximately 25% of the adult population in developed countries suffers from the disease [1]. NAFLD is defined as the presence of >5% fat in the liver without any other liver disease etiologies and/or use of medication, and it includes a histological range from simple steatosis to nonalcoholic steatohepatitis (NASH), which can further progress to cirrhosis and liver cancer [2]. NAFLD is linked to a low molar ratio of hepatic phosphatidylcholine (PC) to phosphatidylethanolamine (PE) [[3], [4], [5]]. PC and PE are the two main phospholipids in plasma membranes of all mammalian cells. In mice, around 70% of hepatic PC is produced via the CDP-choline pathway and the other 30% via phosphatidylethanolamine N-methyltransferase (PEMT) pathway, by which PE is converted to PC via three sequential methylation reactions. PC is the major phospholipid in plasma lipoproteins. PC species derived from both synthesis pathways are crucial for the assembly and secretion of very low-density lipoprotein (VLDL) particles, as deletion of either pathway results in a strong reduction of VLDL secretion [[6], [7], [8], [9]]. Mice lacking PEMT are protected from high-fat diet (HFD)-induced obesity and insulin resistance, but develop severe NASH when fed a HFD, mostly due to impaired VLDL secretion [8,10,11]. Currently, there is no definitive treatment for NALFD, mainly because the precise mechanism underlying the disease and especially its progression to more severe stages is still poorly understood. In Pemt mice, a well-known model for NASH with hepatic fibrosis, it has not been established what the “second hit” is that progresses simple steatosis into hepatic inflammation and fibrosis. One of the lipid classes that have been associated with NASH development is sphingolipids and it is unknown whether sphingolipid metabolism is affected by PEMT-deficiency. Sphingolipids are a major class of membrane lipids that play a fundamental role in membrane architecture and in the regulation of key physiologic processes. Among the sphingolipid family, ceramides have been linked to insulin resistance, oxidative stress, and inflammatory processes [[12], [13], [14], [15], [16], [17], [18]], which suggest that ceramides may play a critical role in development of fatty liver disease [[19], [20], [21], [22]]. Ceramides have been demonstrated to act on the mitochondrial electron transport chain leading to hydrogen peroxide and reactive oxygen species (ROS) generation, thereby inducing oxidative stress and promoting inflammation in different systems [15,[23], [24], [25]]. It is thought that oxidative stress plays a key role contributing to hepatocellular injury. Recent reports have focused on the biological activities of vitamin E in hepatic steatosis development [[26], [27], [28]]. Vitamin E (α-tocopherol) is a lipid-soluble antioxidant that defends cells against radical-induced damage [29]. Vitamin E is absorbed in the intestine, transported in plasma mainly with apolipoprotein B-containing chylomicrons, and transferred to parenchymal cells in liver. Subsequently, vitamin E is secreted from liver, mainly in association with VLDL, to be distributed to other tissues [28]. We have previously demonstrated that livers from HFD-fed Pemt mice exhibit increased oxidative stress [9]; however, its importance in the development of NASH had not been established. Thus, the aims of this study were to investigate whether dietary supplementation of vitamin E can attenuate the development of HFD-induced NASH in Pemt mice, and whether aberrant sphingolipid metabolism is involved in the disease progression in this model.