👤 Nazanin Vaziri

Antipsychotic medications are essential when treating schizophrenia spectrum and other psychotic disorders, but the efficacy and tolerability of these medications vary from person to person. This interindividual variation is likely mediated, at least in part, by epigenomic processes that have yet to be fully elucidated. Herein, we systematically identified and evaluated 65 studies that examine the influence of antipsychotic drugs on epigenomic changes, including global methylation (9 studies), genome-wide methylation (22 studies), candidate gene methylation (16 studies), and histone modification (18 studies). Our evaluation revealed that haloperidol was consistently associated with increased global hypermethylation, which corroborates with genome-wide analyses, mostly performed by methylation arrays. In contrast, clozapine seems to promote hypomethylation across the epigenome. Candidate-gene methylation studies reveal varying effects post-antipsychotic therapy. Some genes like Glra1 and Drd2 are frequently found to undergo hypermethylation, whereas other genes such as SLC6A4, DUSP6, and DTNBP1 are more likely to exhibit hypomethylation in promoter regions. In examining histone modifications, the literature suggests that clozapine changes histone methylation patterns in the prefrontal cortex, particularly elevating H3K4me3 at the Gad1 gene and affecting the transcription of genes like mGlu2 by modifying histone acetylation and interacting with HDAC2 enzymes. Risperidone and quetiapine, however, exhibit distinct impacts on histone marks across different brain regions and cell types, with risperidone reducing H3K27ac in the striatum and quetiapine modifying global H3K9me2 levels in the prefrontal cortex, suggesting antipsychotics demonstrate selective influence on histone modifications, which demonstrates a complex and targeted mode of action. While this review summarizes current knowledge, the intricate dynamics between antipsychotics and epigenetics clearly warrant more exhaustive exploration with the potential to redefine our understanding and treatment of psychiatric conditions. By deciphering the epigenetic changes associated with drug treatment and therapeutic outcomes, we can move closer to personalized medicine in psychiatry. Show less

Chronic kidney disease (CKD) results in hypertriglyceridemia which is largely due to impaired clearance of triglyceride-rich lipoproteins occasioned by downregulation of lipoprotein lipase and very low-density lipoprotein (LDL) receptor in the skeletal muscle and adipose tissue and of hepatic lipase and LDL receptor-related protein in the liver. However, data on the effect of CKD on fatty acid metabolism in the liver is limited and was investigated here. Male Sprague-Dawley rats were randomized to undergo 5/6 nephrectomy (CRF) or sham operation (control) and observed for 12 weeks. The animals were then euthanized and their liver tissue tested for nuclear translocation (activation) of carbohydrate-responsive element binding protein (ChREBP) and sterol-responsive element binding protein-1 (SREBP-1) which independently regulate the expression of key enzyme in fatty acid synthesis, i.e. fatty acid synthase (FAS) and acyl-CoA carboxylase (ACC) as well as nuclear Peroxisome proliferator-activated receptor alpha (PPARα) which regulates the expression of enzymes involved in fatty acid oxidation and transport, i.e. L-FABP and CPT1A. In addition, the expression of ATP synthase α, ATP synthase β, glycogen synthase and diglyceride acyltransferase 1 (DGAT1) and DGAT2 were determined. Compared with controls, the CKD rats exhibited hypertriglyceridemia, elevated plasma and liver tissue free fatty acids, increased nuclear ChREBP and reduced nuclear SREBP-1 and PPARα, upregulation of ACC and FAS and downregulation of L-FABP, CPT1A, ATP synthase α, glycogen synthase and DGAT in the liver tissue. Liver in animals with advanced CKD exhibits ChREBP-mediated upregulation of enzymes involved in fatty acid synthesis, downregulation of PPARα-regulated fatty acid oxidation system and reduction of DGAT resulting in reduced fatty acid incorporation in triglyceride. Show less

Mounting evidence points to lipid accumulation in the diseased kidney and its contribution to progression of nephropathy. We recently found heavy lipid accumulation and marked dysregulation of lipid metabolism in the remnant kidneys of rats with chronic renal failure (CRF). Present study sought to determine efficacy of niacin supplementation on renal tissue lipid metabolism in CRF. Kidney function, lipid content, and expression of molecules involved in cholesterol and fatty acid metabolism were determined in untreated CRF (5/6 nephrectomized), niacin-treated CRF (50 mg/kg/day in drinking water for 12 weeks) and control rats. CRF resulted in hypertension, proteinuria, renal tissue lipid accumulation, up-regulation of scavenger receptor A1 (SR-A1), acyl-CoA cholesterol acyltransferase-1 (ACAT1), carbohydrate-responsive element binding protein (ChREBP), fatty acid synthase (FAS), acyl-CoA carboxylase (ACC), liver X receptor (LXR), ATP binding cassette (ABC) A-1, ABCG-1, and SR-B1 and down-regulation of sterol responsive element binding protein-1 (SREBP-1), SREBP-2, HMG-CoA reductase, PPAR-alpha, fatty acid binding protein (L-FABP), and CPT1A. Niacin therapy attenuated hypertension, proteinuria, and tubulo-interstitial injury, reduced renal tissue lipids, CD36, ChREBP, LXR, ABCA-1, ABCG-1, and SR-B1 abundance and raised PPAR-alpha and L-FABP. Niacin administration improves renal tissue lipid metabolism and renal function and structure in experimental CRF. Show less