Non-Alcoholic Fatty Liver Disease, Diabetes Mellitus, and Zinc/ Zinc Transporters: Is there a Connection?

Immune response and metabolic regulation are closely connected with each other in such a way that dysfunction could lead to a variety of metabolic diseases such as obesity, diabetes mellitus (Dm), lipid metabolism disorders, and fatty liver disorders. Combined with uncritical “sugar-based” overeating and malnutrition, these multisystem metabolic diseases expand into a global epidemic. There are correlations between a fatty liver disease and diabetic metabolism state. A fatty liver leads to insulin resistance and thus to the development of a type 2 Dm; insulin resistance in turn augments the fatty liver. Zinc is a trace element of fundamental importance for a variety of biological processes. The liver is the main organ of the zinc metabolism. Metallothionein and zinc transporters are the key regulators of cellular zinc homeostasis. Molecular studies support the assumption of a correlation between zinc and Dm. Zinc is essential for the synthesis, secretion, and storage of insulin. ZnT8 is a significant autoantigen for type 1 Dm. Genetic polymorphisms in the ZnT8 gene are associated with an increased risk of developing type 2 Dm. Cellular zinc restriction induces the release of stress, particularly in the endoplasmic reticulum (ER). ER stress alone or coupled with cellular stress, as well as chronic inflammation, are central to the development of insulin resistance and type 2 Dm. The present insights into the context of a non-alcoholic fatty liver disease (NAFLD) and a type 2 Dm indicate that zinc and zinc transporters at the cellular level in various forms and in interactions with other mediators both in the regulation of physiological processes and in the formation of pathological processes, such as the cellular and ER stress, as well as chronic inflammation, and the development of metabolic disorders are involved

Albumin substitution in decompensated liver cirrhosis : don’t forget zinc

Decompensated liver cirrhosis has a dismal prognosis, with patients surviving on average for 2–4 years after the first diagnosis of ascites. Albumin is an important tool in the therapy of cirrhotic ascites. By virtue of its oncotic properties, it reduces the risk of cardiovascular dysfunction after paracentesis. Treatment with albumin also counteracts the development of hepatorenal syndrome and spontaneous bacterial peritonitis. More recently, the positive impact of long-term albumin supplementation in liver disease, based on its pleiotropic non-oncotic activities, has been recognized. These include transport of endo- and exogenous substances, anti-inflammatory, antioxidant and immunomodulatory activities, and stabilizing effects on the endothelium. Besides the growing recognition that effective albumin therapy requires adjustment of the plasma level to normal physiological values, the search for substances with adjuvant activities is becoming increasingly important. More than 75% of patients with decompensated liver cirrhosis do not only present with hypoalbuminemia but also with zinc deficiency. There is a close relationship between albumin and the essential trace element zinc. First and foremost, albumin is the main carrier of zinc in plasma, and is hence critical for systemic distribution of zinc. In this review, we discuss important functions of albumin in the context of metabolic, immunological, oxidative, transport, and distribution processes, alongside crucial functions and effects of zinc and their mutual dependencies. In particular, we focus on the major role of chronic inflammatory processes in pathogenesis and progression of liver cirrhosis and how albumin therapy and zinc supplementation may affect these processes

Zinc Deficiency—An Independent Risk Factor in the Pathogenesis of Haemorrhagic Stroke?

Zinc is an essential trace element for human health and plays a fundamental role in metabolic, immunological and many other biological processes. The effects of zinc are based on the intra- and extracellular regulatory function of the zinc ion (Zn2+) and its interactions with proteins. The regulation of cellular zinc homeostasis takes place via a complex network of metal transporters and buffering systems that react to changes in the availability of zinc in nutrition, chronic diseases, infections and many other processes. Zinc deficiency is associated with impairment of numerous metabolic processes, reduced resistance to infections due to impaired immune functions, changes in skin and its appendages and disorders of wound healing and haemostasis. While ischemic heart attacks (myocardial infarction) occur more frequently with meat-based normal diets, haemorrhagic strokes are more frequently observed with vegetarian/vegan diets. The causes are discussed as deficiencies of various micronutrients, such as vitamin B12, vitamin D, various amino acids and also zinc. In the present review, after a description of the functions of zinc and its resorption, a discussion of daily food intake will follow, with a special focus on the importance of food composition and preparation for the zinc balance. The close interrelationships between proteins, especially albumin and zinc will be discussed. Finally, the possible causes and consequences of a zinc deficiency on the blood vessels and blood coagulation are considered

Zinc Aspartate Induces IL-16 Secretion and Apoptosis in Human T Cells

T cell activation mediates immunity to pathogens. On the flipside, T cells are also involved in pathological immune responses during chronic autoimmune diseases. We recently reported that zinc aspartate, a registered drug with high bioavailability, dose-dependently inhibits T cell activation and Th1/Th2/Th17 cytokine production of stimulated human and mouse T cells. To understand the suppressive effect of zinc on T cell function, we here investigated the influence of zinc aspartate on human T cells focusing on the secretion of immunosuppressive cytokines, induction of apoptosis, and caspase 3/7 activity. To this end, we monitored either freshly stimulated or pre-activated human T cells in the presence of zinc aspartate from 40–140 µM over a period of 72 h. Under both experimental conditions, we observed a dose-dependent suppression of human T cell proliferation. While IL-1ra, latent TGF-β1, and IL-10 were dose-dependently reduced, we, unexpectedly, detected elevated levels of IL-16 upon zinc supplementation. In addition, the number of cells with active caspase 3/7 and, consecutively, the amount of cells undergoing apoptosis, steadily increased at zinc aspartate concentrations exceeding 100 µM. Taken together, our findings suggest that zinc aspartate impairs T cell fitness and might be beneficial for the treatment of T cell-mediated autoimmune diseases

Gilbert’s syndrome and antiviral therapy of hepatitis C

Treatment of chronic hepatitis C with type I interferons and ribavirin can be associated with exacerbation of hepatitis and sometimes liver decompensation. We report two patients with chronic hepatitis C virus infection who experienced a severe increase of bilirubin levels of up to 17 times upper the limit of normal value in the absence of deterioration of hepatic function during therapy with pegylated-interferon and ribavirin. A genetic disposition for Gilbert’s syndrome explained the adverse events and permitted a continuation of therapy leading to a sustained clearance of chronic hepatitis C infection. Since one patient jaundiced already during a lead-in treatment period with ribavirin monotherapy we suggest that hyperbilirubinaemia during combination therapy is primarily caused by ribavirin rather than by effects of interferon alpha on UDP-glucuronosyltransferase activities. Of note, both patients recovered from their initial unconjugated hyperbilirubinemia despite continuation of ribavirin therapy, which indicates that compensatory mechanisms leading to a normalization of UGT1A1 activity are likely