A5017019137- Liver Disease and Transplantation
- Liver Disease Diagnosis and Treatment
- Lipid metabolism and biosynthesis
- Drug-Induced Hepatotoxicity and Protection
- Hemophilia Treatment and Research
- Blood properties and coagulation
- Plant biochemistry and biosynthesis
- Blood Coagulation and Thrombosis Mechanisms
- Adipose Tissue and Metabolism
- Hemoglobinopathies and Related Disorders
- Cholesterol and Lipid Metabolism
- Diet, Metabolism, and Disease
- Receptor Mechanisms and Signaling
- Trauma, Hemostasis, Coagulopathy, Resuscitation
- Lipid metabolism and disorders
- Cancer therapeutics and mechanisms
- Organ Transplantation Techniques and Outcomes
- Retinoids in leukemia and cellular processes
- Venous Thromboembolism Diagnosis and Management
- Metabolomics and Mass Spectrometry Studies
- Hormonal and reproductive studies
- Hormonal Regulation and Hypertension
- Genetic Associations and Epidemiology
- RNA modifications and cancer
- Neuroblastoma Research and Treatments
Michigan Medicine
2021-2024
University of Michigan
2021-2023
Michigan State University
2018-2023
Wayne State University
2013-2021
Yecuris (United States)
2021
University of North Carolina at Chapel Hill
2021
Introduction Systemic levels of the anti-inflammatory cytokine interleukin 10 (IL-10) are highest in acetaminophen (APAP)-induced acute liver failure (ALF) patients with poorest prognosis. The mechanistic basis for this counterintuitive finding is not known, as induction IL-10 hypothesized to temper pathological effects immune cell activation. Aberrant production after severe injury could conceivably interfere beneficial, pro-reparative actions cells, such monocytes. Methods To test...
Blood coagulation protease activity is proposed to drive hepatic fibrosis through activation of protease-activated receptors (PARs). Whole-body PAR-1 deficiency reduces experimental fibrosis, and
Regulation of TF (tissue factor):FVIIa (coagulation factor VIIa) complex procoagulant activity is especially critical in tissues where plasma can contact TF-expressing cells. One example the liver, hepatocytes are routinely exposed to because fenestrated sinusoidal endothelium. Although liver-associated contributes coagulation, mechanisms controlling TF:FVIIa this tissue not known. Approach and Results: Common bile duct ligation mice triggered rapid hepatocyte TF-dependent intrahepatic...
Cytosolic sulfotransferase 1C2 (SULT1C2) is expressed in the kidney, stomach, and liver of rats; however, mechanisms regulating expression this enzyme are not known. We evaluated transcriptional regulation SULT1C2 by mevalonate (MVA)-derived intermediates primary cultured rat hepatocytes using several cholesterol synthesis inhibitors. Blocking production with 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor pravastatin (30 <i>μ</i>M), reduced mRNA content ∼40% whereas squalene synthase...
Non-alcoholic fatty liver disease (NAFLD) is caused by excess lipid accumulation in hepatocytes. Genome-wide association studies have identified a strong of NAFLD with non-synonymous E167K amino acid mutation the transmembrane 6 superfamily member 2 (TM6SF2) protein. The reduces TM6SF2 stability, and its carriers display increased hepatic lipids lower serum triglycerides. However, effects on metabolism are not completely understood. We overexpressed wild-type or variant knocked down...
Abstract Background and Aims In severe cases of acetaminophen (APAP) overdose, acute liver injury rapidly progresses to failure (ALF), producing life-threatening complications including, hepatic encephalopathy (HE) multi-organ (MOF). Systemic levels interleukin-6 (IL-6) IL-10 are highest in ALF patients with the most poorest prognosis. The mechanistic basis for dysregulation these cytokines, their association outcome ALF, remain poorly defined. Methods To investigate impact IL-6 we used an...
Farnesyl pyrophosphate (FPP) is a branch-point intermediate in the mevalonate pathway that normally converted mainly to squalene by synthase first committed step of sterol biosynthesis. Treatment with inhibitor squalestatin 1 (SQ1) causes accumulation FPP, its dephosphorylated metabolite farnesol, and several oxidized farnesol-derived metabolites. In addition, SQ1 treatment primary cultured rat hepatocytes increases CYP2B expression through mechanism requires FPP synthesis activation...
Human genome-wide association studies found single-nucleotide polymorphisms (SNPs) near LYPLAL1 (Lysophospholipase-like protein 1) that have sex-specific effects on fat distribution and metabolic traits. To determine whether altering affects obesity disease, we created characterized a mouse knockout (KO) of Lyplal1 . We fed the experimental group mice high-fat, high-sucrose (HFHS) diet for 23 weeks, controls were regular chow diet. Here, show CRISPR-Cas9 whole-body KO an HFHS showed...
Non‐alcoholic fatty liver disease is one the most common metabolic syndromes characterized by accumulation of triglycerides (TG) in liver. Treatment with endogenous isoprenoid farnesol lowers hepatic TG levels rodents, and this effect appears to involve at least two nuclear receptors, peroxisome proliferator‐activated receptor α farnesoid X (FXR). Activation constitutive androstane (CAR) has also been shown ameliorate steatosis rodents. However, farnesol’s effects on human lipid metabolism...
The squalene synthase inhibitor squalestatin 1 (Squal1) is a potent and efficacious inducer of CYP2B expression in primary cultured rat hepatocytes liver. To determine whether Squal1 also an human CYP2B, the effects treatment were evaluated hepatocytes, differentiated HepaRG cells, humanized mouse livers. did not increase CYP2B6 mRNA levels or cells only slightly inconsistently increased content However, with farnesol, which mediates Squal1's effect on expression, expressing constitutive...
Abstract Human genome-wide association studies found SNPs near LYPLAL1 that have sex-specific effects on fat distribution and metabolic traits. To determine whether altering affects obesity disease we created characterized a mouse knockout of Lyplal1 . Here show CRISPR-Cas9 whole-body (KO) mice fed high fat, sucrose (HFHS) diet showed differences in weight gain accumulation. Female, not male, KO weighed less than WT mice, had reduced body percentage, white mass, adipocyte diameter accounted...
Inhibition of squalene synthase causes accumulation farnesyl pyrophosphate (FPP) in primary cultured rat hepatocytes, which increases CYP2B expression through activation the constitutive androstane receptor (CAR). However, identity CAR‐activating isoprenoid has not been established. Since lipid phosphatase PPAPDC2 recently reported to catalyze FPP dephosphorylation (Miriyala et al., J Biol Chem 285:13918–13929, 2010), we determined effect overexpression and knockdown on squalestatin 1...
Acetaminophen overdose is the leading cause of acute liver failure in United States. In mice, interleukin‐10 (IL‐10) deficiency dramatically increased early inflammation and hepatotoxicity after acetaminophen challenge. Paradoxically, IL‐10 levels are highest patients with poorest prognosis. The mechanistic basis for this apparent discrepancy not understood. We examined function a mouse model that recapitulates failed repair analogous to patients, wherein mice treated large dose (i.e., 600...