ABSTRACT
BACKGROUND: Endoplasmic reticulum (ER) stress-mediated increases in the hepatic levels of the very low-density lipoprotein (VLDL) receptor (VLDLR) promote hepatic steatosis by increasing the delivery of triglyceride-rich lipoproteins to the liver. Here, we examined whether the NAD(+)-dependent deacetylase sirtuin 1 (SIRT1) regulates hepatic lipid accumulation by modulating VLDLR levels and the subsequent uptake of triglyceride-rich lipoproteins. METHODS: Rats fed with fructose in drinking water, Sirt1-/- mice, mice treated with the ER stressor tunicamycin with or without a SIRT1 activator, and human Huh-7 hepatoma cells transfected with siRNA or exposed to tunicamycin or different inhibitors were used. RESULTS: Hepatic SIRT1 protein levels were reduced, while those of VLDLR were upregulated in the rat model of metabolic dysfunction-associated steatotic liver disease (MASLD) induced by fructose-drinking water. Moreover, Sirt1-/- mice displayed increased hepatic VLDLR levels that were not associated with ER stress, but were accompanied by an increased expression of hypoxia-inducible factor 1α (HIF-1α)-target genes. The pharmacological inhibition or gene knockdown of SIRT1 upregulated VLDLR protein levels in the human Huh-7 hepatoma cell line, with this increase abolished by the pharmacological inhibition of HIF-1α. Finally, SIRT1 activation prevented the increase in hepatic VLDLR protein levels in mice treated with the ER stressor tunicamycin. CONCLUSIONS: Overall, these findings suggest that SIRT1 attenuates fatty liver development by modulating hepatic VLDLR levels.
Subject(s)
Liver , Receptors, LDL , Sirtuin 1 , Animals , Sirtuin 1/metabolism , Sirtuin 1/genetics , Humans , Liver/metabolism , Liver/drug effects , Receptors, LDL/metabolism , Receptors, LDL/genetics , Mice , Male , Endoplasmic Reticulum Stress/drug effects , Rats , Cell Line, Tumor , Mice, Knockout , Fatty Liver/metabolism , Fatty Liver/genetics , Fatty Liver/pathology , Mice, Inbred C57BL , Tunicamycin/pharmacology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Rats, Sprague-DawleyABSTRACT
BACKGROUND: Hypersensitivity reactions to the nonspecific proteinase inhibitor aprotinin may occur. The present study evaluates the incidence of hypersensitivity reactions to aprotinin. METHODS: Data were prospectively collected as part of the institution's quality assurance program. The database was screened for anaphylactic reactions, especially those against aprotinin. The definition of an allergic reaction was predefined. A severe reaction was defined as hemodynamic instability of more than 10 minutes despite high dosages of vasopressors and inotropic medication. RESULTS: Of 13,315 cardiac operations, 12,403 were done with aprotinin, with 801 reexposures in 697 patients. Eleven reactions to aprotinin (11 of 11,602; 0.09%, 95% confidence interval: 0.05% to 0.16%) were recorded after primary exposure, of which none was severe, while 12 reactions (12 of 801; 1.5%; 95% confidence interval: 0.86% to 2.6%) occurred after reexposure, of which 5 were severe. All severe reactions were in patients reexposed to aprotinin within 6 months after previous exposure. There was no reaction observed in patients reexposed to aprotinin within 3 days after the last exposure (n = 42). The incidence of hypersensitivity reactions was 4.1%, 1.9%, and 0.4% in the less than 6 months, 6 to 12 months, and more than 12 months reexposure intervals, respectively. CONCLUSIONS: The risk of hypersensitivity reactions is low after primary exposure to aprotinin. This risk after reexposure reaches a maximum between the fourth day and the 30th day after previous exposure and declines considerably after 6 months. Consequently, application of aprotinin carries a high risk between the fourth and the 30th day after previous exposure, and cannot be recommended for the first 6 months, but is justifiable in previously aprotinin-exposed patients with a high risk of bleeding after this interval.
