Role of Bile Acids in Liver Injury and Regeneration following Acetaminophen Overdose

Bile acids play a critical role in liver injury and regeneration, but their role in acetaminophen (APAP)–induced liver injury is not known. We tested the effect of bile acid modulation on APAP hepatotoxicity using C57BL/6 mice, which were fed a normal diet, a 2% cholestyramine (CSA)–containing diet for bile acid depletion, or a 0.2% cholic acid (CA)–containing diet for 1 week before treatment with 400 mg/kg APAP. CSA-mediated bile acid depletion resulted in significantly higher liver injury and delayed regeneration after APAP treatment. In contrast, 0.2% CA supplementation in the diet resulted in a moderate delay in progression of liver injury and significantly higher liver regeneration after APAP treatment. Either CSA-mediated bile acid depletion or CA supplementation did not affect hepatic CYP2E1 levels or glutathione depletion after APAP treatment. CSA-fed mice exhibited significantly higher activation of c-Jun N-terminal protein kinases and a significant decrease in intestinal fibroblast growth factor 15 mRNA after APAP treatment. In contrast, mice fed a 0.2% CA diet had significantly lower c-Jun N-terminal protein kinase activation and 12-fold higher fibroblast growth factor 15 mRNA in the intestines. Liver regeneration after APAP treatment was significantly faster in CA diet–fed mice after APAP administration secondary to rapid cyclin D1 induction. Taken together, these data indicate that bile acids play a critical role in both initiation and recovery of APAP-induced liver injury.Bile acids are versatile biological molecules that regulate energy homeostasis, activate nuclear receptors and cell signaling pathways, and control cell proliferation and inflammatory processes in the liver and gastrointestinal tract.^1,2 Bile acids maintain their own homeostasis by activating a complex signaling network involving hepatic and intestinal farnesoid X receptor (FXR), small heterodimer partner, and intestinal fibroblast growth factor (FGF) 15 (FGF19 in human) expression, culminating in inhibition of the primary bile acid–synthesizing enzyme, CYP7A1.^3–6 Although bile acids are potent signaling molecules at pathophysiological concentrations, they cause apoptosis, necrosis, and oxidative stress.^3,7–10 Bile acids have also been implicated in stimulation of liver regeneration.^11–14 Studies in recent years indicate that the bile acid–mediated gut-liver signaling axis may play a critical role in regulation of liver homeostasis.^6,15,16Acetaminophen (APAP) is the most commonly used analgesic and antipyretic agent.¹⁷ An overdose of APAP is the major cause of acute liver failure in the United States.^18,19 The mechanisms of APAP-induced liver injury and subsequent liver regeneration are the focus of intense investigation.^20–22 In an overdose situation, excess APAP is mainly metabolized by CYP2E1 to a reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI). In hepatocytes, conjugation of NAPQI to GSH is the key mechanism for detoxification of NAPQI. Once the GSH is depleted, NAPQI attacks cellular proteins, especially mitochondrial proteins, to form protein adducts. This triggers a cascade of intracellular signaling events involving c-Jun N-terminal protein kinase (JNK) activation and mitochondrial permeability transition, finally culminating in necrotic cell death.²⁰ Liver injury is followed by compensatory liver regeneration, which is a critical determinant of final outcome of liver injury.²³ Despite decades of research, how these intracellular events are affected by extracellular signaling is not known.The current study was designed to explore the role of bile acids in initiation of liver injury and stimulation of liver regeneration after APAP overdose. These studies are highly significant because the data reveal a novel role of bile acids in cellular protection and liver regeneration after APAP overdose, and these studies investigate the effect of resin-mediated bile acid depletion, a commonly used therapy, on APAP toxicity.     

Apolipoprotein E and familial longevity

Exceptional longevity is associated with substantial heritability. The ?4 allele in apolipoprotein E and the linked G allele in rs2075650 of TOMM40 have been associated with increased mortality and the ?2 allele with decreased mortality, although inconsistently. Offspring from long-lived families and spouse controls were recruited at 3 sites in the United States and Denmark. We used generalized estimating equations to compare the likelihood of carrying risk alleles in offspring (n = 2307) and spouse controls (n = 764), adjusting for age, sex, level of education, and family membership. The likelihood of carrying an APOE ?4 allele or a G allele in rs2075650 was lower (odds ratio [OR], 0.75; p = 0.005 and OR, 0.70; p = 0.002) and the likelihood of carrying an APOE ?2 allele was higher (OR, 1.5; p = 0.007) among family members in the offspring generation than among their spouse controls. Our findings support the hypothesis that both reduction in the frequency of the ?4 allele and increase in the frequency of the ?2 allele contribute to longevity.     

Immunohistochemical validation of INI1/SMARCB1 in a spectrum of musculoskeletal tumors: An experience at a Tertiary Cancer Referral Centre

The purpose of this study was to evaluate and validate immunohistochemical (IHC) expression of INI1/SMARCB1 in various musculoskeletal tumors in the light of the established literature.     

Identification of a Novel NDM Variant,NDM-13, from a Multidrug-Resistant Escherichia coli Clinical Isolate in Nepal

A novel New Delhi metallo-β-lactamase, NDM-13, was identified in a carbapenem-resistant Escherichia coli clinical isolate obtained from the urine of a patient in Nepal. The enzymatic activity of NDM-13 against β-lactams was similar to that of NDM-1. However, NDM-13 displayed significantly higher k_cat/K_m ratios for cefotaxime. The genetic environment of bla_NDM-13 was determined to be tnpA-IS30-bla_NDM-13-ble_MBL-trpF-dsbC-cutA-groES-groL, with bla_NDM-13 located within the chromosome.     

Biomarker System for Genetic Analysis of Stored Grain Pests Callosobruchus maculatus and Callosobruchus chinensis

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - Random amplified polymorphic DNA-PCR (RAPD-PCR) analysis was used in combination with morphological...