Indiana University-Purdue University Indianapolis (IUPUI) / Liver fibrosis is the result of different types of chronic liver diseases, such as cholestatic liver disease and nonalcoholic steatohepatitis, among others. Fibrosis, if left unchecked, may progress to the point of cirrhosis – permanently affecting liver function detrimentally and potentially leading to development of hepatocellular carcinoma. Inflammatory response following tissue injury is vital for the initiation of fibrosis; chronic inflammation results in abnormal tissue healing and promotes a pro-fibrogenic response. Activins are cytokines that have been identified as members of the TGFβ superfamily of growth and differentiation factors. Activin A and B, in particular, have been identified as having roles in the pathophysiology of liver disease, but have not been investigated thoroughly. We treated mice with concanavalin A, a potent T-cell mitogen with liver specificity when administered intravenously, and characterized the resulting response to liver injury and how activin A and B are modulated during this acute inflammatory phase. We showed that activin B is highly increased in circulation following inflammation, as well as locally in the liver as well as the spleen. We then neutralized activin A and B via neutralizing antibodies in our concanavalin A-induced liver injury model to determine if inhibition of these ligands may confer protective effects during the acute inflammatory response in liver. Neutralization of either activin A or activin B protected hepatocytes, improved liver function, and significantly reduced circulating cytokines following concanavalin A administration. Finally, we determined whether inhibition of activin A or B might prevent or reverse the development of liver fibrosis after disease has been established. We induced liver fibrosis in mice via the hepatotoxin carbon tetrachloride, and then treated with neutralizing antibodies while still maintaining carbon tetrachloride administration. Neutralization of activin A and B markedly reduced liver fibrosis, protected hepatocytes, and improved liver function. Our findings implicate both activin A and B as major players in the acute inflammatory response to liver injury, as well as during chronic injury and fibrogenesis, and demonstrate the therapeutic potential of targeting these ligands for the treatment of fibrosis in chronic liver diseases.

Indiana University-Purdue University Indianapolis (IUPUI) / The maternal liver exhibits robust adaptations to pregnancy to accommodate the metabolic needs of developing and growing placenta and fetus by largely unknown mechanisms. We found that achaete-scute homolog 1 (Ascl1), a basic helix-loop-helix transcription factor essential for neuronal development, is highly activated in maternal hepatocytes during the second half of gestation in mice. Our aim is to investigate whether and how Ascl1 plays a pregnancy-dependent role. We deleted the Ascl1 gene in the maternal liver using three independent mouse models from mid-gestation until term and identified multiple Ascl1-dependent phenotypes. When Ascl1 was deficient in maternal hepatocytes, maternal livers exhibited aberrant hepatocyte histology, fat accumulation, increased hepatocyte cell cycle, and enlarged size, accompanied by reduced albumin production and elevated levels of free fatty acids, ALT, and AST in the maternal blood, indicating maternal liver dysfunction. In the same situation, maternal spleen and pancreas displayed marked enlargement without an overt structural change; the placenta exhibited striking overgrowth with increased ALP production; and the cecal microbiome showed alterations in the relative abundance of several bacterial subpopulations. Moreover, litters born from maternal hepatic Ascl1 null mutated dam experienced abnormal postnatal growth after weaning. RNA-seq analysis revealed Ascl1-regulated genes in the maternal liver associated with Ascl1-dependent phenotypes. Of particular interest, we found that, in maternal hepatocytes, Ascl1 loss-of-function caused the activation of paternally imprinted gene insulin-like growth factor 2 (Igf2) encoding a major placental and fetal growth factor. IGF2 is also a known mitogen for hepatocytes and several hematopoietic lineages. Thus, IGF2 is a potential inducer of Ascl1-dependent phenotypes including placental overgrowth and maternal organ enlargement. Our studies revealed Ascl1 as a novel regulator of maternal liver physiology during pregnancy. Ascl1 activation in maternal hepatocytes is essential for normal placental growth and appropriate maternal organ adaptations, ensuring the health of both the mother and the fetus.

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Type 2 diabetes mellitus (T2D) is a metabolic disease characterized by hyperglycemia, insulin resistance, dyslipidemia, and beta cell dysfunction. T2D prevalence has been increasing with not all clear causes identified, while the use of synthetic chemicals has risen. Because genetics can only explain a small percentage of disease development, more attention is being given to associations of environmental chemical exposure and disease. Epidemiological evidence suggests environmental exposure to organochlorine compounds (OC) including dichlorodiphenyltrichloroethane (DDT) and its bioaccumulative metabolite dichlorodiphenyldichloroethylene (DDE) is associated with T2D prevalence and is hypothesized to play a role in contributing to T2D. The purpose of this research was to perform anin vitro study of DDE exposure and its effect on liver hepatocyte and pancreatic beta cell functions that regulate biochemical markers implicated in T2D, and determine an association of DDE exposure with T2D from a population exhibiting a high prevalence of T2D living in an area once highly exposed to OC. Human blood samples from diabetics and non-diabetics were analyzed for any significant association of DDE levels with biochemical markers of T2D and T2D presence. The in vitro effect of DDE exposure on the regulation of hepatocyte lipid metabolism and secretion with respect to triglyceride (TG), apolipoprotein B (ApoB), sortilin-1 (Sort-1), and microsomal triglyceride transfer protein (MTP) levels implicated in dyslipidemia was investigated. Finally, the in vitro effect of DDE exposure on the regulation of beta cell insulin secretion with respect to insulin, oxidative stress (ROS), prohormone convertase (PC), and pancreatic-duodenal homeobox-1(PDX-1) levels implicated in beta cell dysfunction was investigated. Based on our results, DDE levels were not associated with an increased risk of T2D prevalence from this study population, although DDE levels were correlated with some biochemical markers of T2D. ApoB secretion, Sort-1 and MTP levels were increased after DDE exposure, while TG accumulation was decreased in hepatocytes. Insulin secretion and PC levels were increased after DDE exposure, while ROS and PDX-1 levels were increased but not significantly. Although no causative association of DDE exposure with T2D prevalence was found, a potential mechanism of DDE’s effect on regulating biochemical markers of T2D was identified.

A new potent competitive inhibitor of glyoxalase II, S-carbobenzoxglutathione (CBG) (Ki=0.065mM) was synthesized. The homogenous enzyme was obtained by a simple two-step CBG-affinity column chromatographic procedure.

It was the purpose of this study to purify glyoxalase I and then characterize its physical and kinetic properties. A comparison of the enzyme from the liver of normal and tumor-bearing mice and from the tumor itself was also to be made.

Background: Liver injury is the most common severe adverse effect of first-line anti-tuberculosis therapy (ATT). Nacetylcysteine (NAC) has efficacy in patients with paracetamol toxicity, and may be of benefit in liver injury due to other causes, such as ATT-induced liver injury (AT-DILI). Rechallenge of first line ATT after liver injury is usually attempted and may result in recurrence of liver injury. Alanine transaminase (ALT) is the biomarker currently used in AT-DILI diagnosis. MicroRNA-122 (miR-122) is a sensitive biomarker for liver injury due to paracetamol, but data on utility as a biomarker for ATDILI are limited. Methods: We conducted a randomized double-blind placebo-controlled trial of intravenous NAC in adult hospitalized participants with AT-DILI. Primary endpoint was time to ALT < 100 U/L; secondary endpoints included length of hospital stay and 8-week mortality. We described outcomes of ATT rechallenge following AT-DILI. We quantified miR-122 and ALT concentrations before and after infusion of NAC/placebo, and explored the effect of NAC on miR-122. Results We enrolled 102 participants with AT-DILI, 53 randomized to NAC and 49 to placebo. Mean age was 38 (SD±10) years, 58 (57%) were female and 89 (87%) were HIV positive. Median time to ALT

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