130 results match your criteria lko mice

Hepatic SENP2 Controls Systemic Metabolism via SUMOylation-dependent Regulation of Liver-Adipose Tissue Crosstalk.

Hepatology 2021 May 2. Epub 2021 May 2.

Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai, 200032, China.

Background & Aims: Nonalcoholic fatty liver disease (NAFLD), characterized by aberrant triglycerides accumulation in liver, affects the metabolism remodeling of hepatic and non-hepatic tissues by secreting altered hepatokines. SUMO-specific protease 2 (SENP2) is responsible for de-SUMOylation of target protein, with broad effects on cell growth, signal transduction and developmental process. However, role of SENP2 in hepatic metabolism remains unclear. Read More

View Article and Full-Text PDF

Integrated Action of Autophagy and Adipose Tissue Triglyceride Lipase Ameliorates Diet-Induced Hepatic Steatosis in Liver-Specific PLIN2 Knockout Mice.

Cells 2021 Apr 25;10(5). Epub 2021 Apr 25.

Obesity and Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA.

An imbalance in the storage and breakdown of hepatic lipid droplet (LD) triglyceride (TAG) leads to hepatic steatosis, a defining feature of non-alcoholic fatty liver disease (NAFLD). The two primary cellular pathways regulating hepatic TAG catabolism are lipolysis, initiated by adipose triglyceride lipase (ATGL), and lipophagy. Each of these processes requires access to the LD surface to initiate LD TAG catabolism. Read More

View Article and Full-Text PDF

BRG1 Links TLR4 Trans-Activation to LPS-Induced SREBP1a Expression and Liver Injury.

Front Cell Dev Biol 2021 18;9:617073. Epub 2021 Mar 18.

Key Laboratory of Targeted Invention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.

Multiple organ failure is one of the most severe consequences in patients with septic shock. Liver injury is frequently observed during this pathophysiological process. In the present study we investigated the contribution of Brahma related gene 1 (BRG1), a chromatin remodeling protein, to septic shock induced liver injury. Read More

View Article and Full-Text PDF

BIR repeat-containing ubiquitin conjugating enzyme (BRUCE) regulation of β-catenin signaling in the progression of drug-induced hepatic fibrosis and carcinogenesis.

World J Hepatol 2021 Mar;13(3):343-361

Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45267, United States.

Background: BIR repeat-containing ubiquitin conjugating enzyme (BRUCE) is a liver tumor suppressor, which is downregulated in a large number of patients with liver diseases. BRUCE facilitates DNA damage repair to protect the mouse liver against the hepatocarcinogen diethylnitrosamine (DEN)-dependent acute liver injury and carcinogenesis. While there exists an established pathologic connection between fibrosis and hepatocellular carcinoma (HCC), DEN exposure alone does not induce robust hepatic fibrosis. Read More

View Article and Full-Text PDF

The Mediator complex kinase module is necessary for fructose regulation of liver glycogen levels through induction of glucose-6-phosphatase catalytic subunit (G6pc).

Mol Metab 2021 Mar 31;48:101227. Epub 2021 Mar 31.

Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, 10461, USA; Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA; Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.

Objective: Liver glycogen levels are dynamic and highly regulated by nutrient availability as the levels decrease during fasting and are restored during the feeding cycle. However, feeding in the presence of fructose in water suppresses glycogen accumulation in the liver by upregulating the expression of the glucose-6-phosphatase catalytic subunit (G6pc) gene, although the exact mechanism is unknown. We generated liver-specific knockout MED13 mice that lacked the transcriptional Mediator complex kinase module to examine its effect on the transcriptional activation of inducible target gene expression, such as the ChREBP- and FOXO1-dependent control of the G6pc gene promoter. Read More

View Article and Full-Text PDF

Reptin/RUVBL2 is required for hepatocyte proliferation in vivo, liver regeneration and homeostasis.

Liver Int 2021 Mar 31. Epub 2021 Mar 31.

INSERM, UMR1053, Bordeaux, France.

Previous studies have shown that Reptin is overexpressed in hepatocellular carcinoma and that it is necessary for in vitro proliferation and cell survival. However, its pathophysiological role in vivo remains unknown. We aimed to study the role of Reptin in hepatocyte proliferation after regeneration using a liver Reptin knock-out model (Reptin ). Read More

View Article and Full-Text PDF

Differential roles of GDF15 and FGF21 in systemic metabolic adaptation to the mitochondrial integrated stress response.

iScience 2021 Mar 12;24(3):102181. Epub 2021 Feb 12.

Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwaro, Daejeon 35015, Republic of Korea.

Perturbation of mitochondrial proteostasis provokes cell autonomous and cell non-autonomous responses that contribute to homeostatic adaptation. Here, we demonstrate distinct metabolic effects of hepatic metabokines as cell non-autonomous factors in mice with mitochondrial OxPhos dysfunction. Liver-specific mitochondrial stress induced by a loss-of-function mutation in (LKO) leads to aberrant oxidative phosphorylation and promotes the mitochondrial unfolded protein response. Read More

View Article and Full-Text PDF

Hepatic HuR protects against the pathogenesis of non-alcoholic fatty liver disease by targeting PTEN.

Cell Death Dis 2021 Mar 4;12(3):236. Epub 2021 Mar 4.

The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

The liver plays an important role in lipid and glucose metabolism. Here, we show the role of human antigen R (HuR), an RNA regulator protein, in hepatocyte steatosis and glucose metabolism. We investigated the level of HuR in the liver of mice fed a normal chow diet (NCD) and a high-fat diet (HFD). Read More

View Article and Full-Text PDF

Liver specific deletion of mouse Tm6sf2 promotes steatosis, fibrosis and hepatocellular cancer.

Hepatology 2021 Feb 27. Epub 2021 Feb 27.

Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, United States.

Background And Aims: Human TM6SF2 variant rs58542926 is associated with nonalcoholic fatty liver disease (NAFLD) and hepatocellular cancer (HCC). However, conflicting reports in germline Tm6sf2 knockout mice suggest no change or decreased VLDL secretion and either unchanged or increased hepatic steatosis, with no increased fibrosis. We generated liver specific Tm6Sf2 knockout mice (Tm6 LKO) to study VLDL secretion and the impact on development and progression of NAFLD. Read More

View Article and Full-Text PDF
February 2021

Regulation of hepatic circadian metabolism by the E3 ubiquitin ligase HRD1-controlled CREBH/PPARα transcriptional program.

Mol Metab 2021 Feb 13;49:101192. Epub 2021 Feb 13.

Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA; Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, MI 48201, USA; NanoBioScience Institute, Wayne State University, Detroit, MI 48201, USA. Electronic address:

Objective: The endoplasmic reticulum (ER)-resident E3 ligase HRD1 and its co-activator Sel1L are major components of ER-associated degradation (ERAD) machinery. Here, we investigated the molecular mechanism and functional significance underlying the circadian regulation of HRD1/Sel1L-mediated protein degradation program in hepatic energy metabolism.

Methods: Genetically engineered animal models as well as gain- and loss-of-function studies were employed to address the circadian regulatory mechanism and functional significance. Read More

View Article and Full-Text PDF
February 2021

BRG1 Mediates Nephronectin Activation in Hepatocytes to Promote T Lymphocyte Infiltration in ConA-Induced Hepatitis.

Front Cell Dev Biol 2020 21;8:587502. Epub 2021 Jan 21.

Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medicine, Nanjing, China.

Fulminant hepatitis (FH) is a major cause of acute liver failure. Concanavalin A (ConA) belongs to the lectin family and is frequently used as an inducer of FH in animal models. ConA induced FH is characterized by massive accumulation of T lymphocytes in the liver. Read More

View Article and Full-Text PDF
January 2021

Osteocalcin Alleviates Nonalcoholic Fatty Liver Disease in Mice through GPRC6A.

Int J Endocrinol 2021 15;2021:9178616. Epub 2021 Jan 15.

Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai 200233, China.

Osteocalcin is a bone-derived hormone that plays an important role in the crosstalk between bone and energy metabolism. Previous studies have found that treatment with uncarboxylated osteocalcin can protect mice from high-fat diet-induced nonalcoholic fatty liver disease (NAFLD). However, the potential mechanisms remain unclear. Read More

View Article and Full-Text PDF
January 2021

CD73 Maintains Hepatocyte Metabolic Integrity and Mouse Liver Homeostasis in a Sex-Dependent Manner.

Cell Mol Gastroenterol Hepatol 2021 Jan 29;12(1):141-157. Epub 2021 Jan 29.

Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Electronic address:

Background & Aims: Metabolic imbalance and inflammation are common features of chronic liver diseases. Molecular factors controlling these mechanisms represent potential therapeutic targets. CD73 is the major enzyme that dephosphorylates extracellular adenosine monophosphate (AMP) to form the anti-inflammatory adenosine. Read More

View Article and Full-Text PDF
January 2021

Deletion of Sox9 in the liver leads to hepatic cystogenesis in mice by transcriptionally downregulating Sec63.

J Pathol 2021 May 5;254(1):57-69. Epub 2021 Mar 5.

Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, PR China.

Hepatic cysts are found in heterogeneous disorders with different pathogeneses, of which simple hepatic cysts and polycystic liver diseases are two major types. The process of hepatic cytogenesis for these two diseases is caused by defects in remodelling of the ductal plate during biliary tract development, which is called ductal plate malformation. SOX9 is a transcription factor participating in the process of bile duct development, and thus, its dysregulation may play important roles in hepatic cystogenesis. Read More

View Article and Full-Text PDF

Myeloid TBK1 Deficiency Induces Motor Deficits and Axon Degeneration Through Inflammatory Cell Infiltration.

Mol Neurobiol 2021 May 13;58(5):2435-2446. Epub 2021 Jan 13.

Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People's Republic of China.

Background: TANK-binding kinase1 (TBK1) haploinsufficiency has been shown to cause both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); however, the mechanism is unclear.

Methods: Myeloid Tbk1 knockout mice (Tbk1-LKO mice) were established and motor function and pathological analyses were also performed. The level of p-TBK1 was analyzed in the ALS animal model and in patient samples using flow cytometry. Read More

View Article and Full-Text PDF

"Structural imprinting" of the cutaneous immune effector function.

Tissue Barriers 2021 Jan 3;9(1):1851561. Epub 2020 Dec 3.

Department of Dermatology, Osaka University Graduate School of Medicine , Osaka, Japan.

Keratinization provides tolerance to desiccation and mechanical durability. Loricrin, which is an epidermal thiol-rich protein, efficiently stabilizes terminally differentiated keratinocytes and maintains redox homeostasis. The discovery of the largely asymptomatic loricrin knockout (LKO) phenotype decades ago was rather unpredicted. Read More

View Article and Full-Text PDF
January 2021

Alcohol and Liver Clock Disruption Increase Small Droplet Macrosteatosis, Alter Lipid Metabolism and Clock Gene mRNA Rhythms, and Remodel the Triglyceride Lipidome in Mouse Liver.

Front Physiol 2020 7;11:1048. Epub 2020 Sep 7.

Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States.

Heavy alcohol drinking dysregulates lipid metabolism, promoting hepatic steatosis - the first stage of alcohol-related liver disease (ALD). The molecular circadian clock plays a major role in synchronizing daily rhythms in behavior and metabolism and clock disruption can cause pathology, including liver disease. Previous studies indicate that alcohol consumption alters liver clock function, but the impact alcohol or clock disruption, or both have on the temporal control of hepatic lipid metabolism and injury remains unclear. Read More

View Article and Full-Text PDF
September 2020

Hepatic E4BP4 induction promotes lipid accumulation by suppressing AMPK signaling in response to chemical or diet-induced ER stress.

FASEB J 2020 10 11;34(10):13533-13547. Epub 2020 Aug 11.

Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.

Prolonged ER stress has been known to be one of the major drivers of impaired lipid homeostasis during the pathogenesis of non-alcoholic liver disease (NAFLD). However, the downstream mediators of ER stress pathway in promoting lipid accumulation remain poorly understood. Here, we present data showing the b-ZIP transcription factor E4BP4 in both the hepatocytes and the mouse liver is potently induced by the chemical ER stress inducer tunicamycin or by high-fat, low-methionine, and choline-deficient (HFLMCD) diet. Read More

View Article and Full-Text PDF
October 2020

AMPK activator C24 inhibits hepatic lipogenesis and ameliorates dyslipidemia in HFHC diet-induced animal models.

Acta Pharmacol Sin 2021 Apr 28;42(4):585-592. Epub 2020 Jul 28.

Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.

Dyslipidemia is a chronic metabolic disease characterized by elevated levels of lipids in plasma. Recently, various studies demonstrate that the increased activity of adenosine 5'-monophosphate-activated protein kinase (AMPK) causes health benefits in energy regulation. Thus, great efforts have been made to develop AMPK activators as a metabolic syndrome treatment. Read More

View Article and Full-Text PDF

Hepatic peroxisomal β-oxidation suppresses lipophagy via RPTOR acetylation and MTOR activation.

Autophagy 2020 09 27;16(9):1727-1728. Epub 2020 Jul 27.

Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine , St. Louis, MO, USA.

Hepatic lipid homeostasis is controlled by a coordinated regulation of various metabolic pathways involved in de novo synthesis, uptake, storage, and catabolism of lipids. Disruption of this balance could lead to hepatic steatosis. Peroxisomes play an essential role in lipid metabolism, yet their importance is often overlooked. Read More

View Article and Full-Text PDF
September 2020

Liver-specific Prkn knockout mice are more susceptible to diet-induced hepatic steatosis and insulin resistance.

Mol Metab 2020 11 10;41:101051. Epub 2020 Jul 10.

Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

Objective: PARKIN is an E3 ubiquitin ligase that regulates mitochondrial quality control through a process called mitophagy. Recent human and rodent studies suggest that loss of hepatic mitophagy may occur during the pathogenesis of obesity-associated fatty liver and contribute to changes in mitochondrial metabolism associated with this disease. Whole-body Prkn knockout mice are paradoxically protected against diet-induced hepatic steatosis; however, liver-specific effects of Prkn deficiency cannot be discerned in this model due to pleotropic effects of germline Prkn deletion on energy balance and subsequent protection against diet-induced obesity. Read More

View Article and Full-Text PDF
November 2020

Anti-psoriatic effect of Lavandula angustifolia essential oil and its major components linalool and linalyl acetate.

J Ethnopharmacol 2020 Oct 3;261:113127. Epub 2020 Jul 3.

CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, 226015, UP, India. Electronic address:

Ethno-pharmacological Relevance: Lavender oil (LO) is an aromatic/essential oil extracted from Lavandula angustifolia and traditionally used as an aromatherapy massage oil due to its anti-inflammatory and wound healing property and also for providing the relief in other skin conditions such as psoriasis, dermatitis and eczema. However, LO has not been evaluated scientifically for psoriasis like skin inflammation.

Aim Of The Study: This study was aimed to investigate the LO and its major components linalool (L) and linalyl acetate (LA) against psoriasis like skin inflammation. Read More

View Article and Full-Text PDF
October 2020

The unfolded protein response regulates hepatic autophagy by sXBP1-mediated activation of TFEB.

Autophagy 2020 Jul 15:1-15. Epub 2020 Jul 15.

Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA.

Defective macroautophagy/autophagy and a failure to initiate the adaptive unfolded protein response (UPR) in response to the endoplasmic reticulum (ER) stress contributes to obesity-associated metabolic dysfunction. However, whether and how unresolved ER stress leads to defects in the autophagy pathway and to the progression of obesity-associated hepatic pathologies remains unclear. Obesity suppresses the expression of hepatic spliced XBP1 (X-box binding protein 1; sXBP1), the key transcription factor that promotes the adaptive UPR. Read More

View Article and Full-Text PDF

Liver-specific knockout of B cell lymphoma 6 suppresses progression of non-alcoholic steatohepatitis in mice.

Sci Rep 2020 06 16;10(1):9704. Epub 2020 Jun 16.

Department of Molecular Life Sciences, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, Japan, 259-1193.

The prevalence of non-alcoholic steatohepatitis (NASH) rapidly increases with metabolic disorders such as dyslipidaemia, high blood pressure, and hyperglycaemia. B cell lymphoma 6 (Bcl6), a transcriptional repressor, is essential for the formation of germinal centre B cells. In this study, we analysed the role of Bcl6 in NASH progression-associated pathological changes, such as hepatic lipid accumulation, liver fibrosis, and hepatocarcinogenesis. Read More

View Article and Full-Text PDF

Acetyl-CoA Derived from Hepatic Peroxisomal β-Oxidation Inhibits Autophagy and Promotes Steatosis via mTORC1 Activation.

Mol Cell 2020 07 29;79(1):30-42.e4. Epub 2020 May 29.

Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Autophagy is activated by prolonged fasting but cannot overcome the ensuing hepatic lipid overload, resulting in fatty liver. Here, we describe a peroxisome-lysosome metabolic link that restricts autophagic degradation of lipids. Acyl-CoA oxidase 1 (Acox1), the enzyme that catalyzes the first step in peroxisomal β-oxidation, is enriched in liver and further increases with fasting or high-fat diet (HFD). Read More

View Article and Full-Text PDF

Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis.

Blood 2020 08;136(6):726-739

The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.

Although the serum-abundant metal-binding protein transferrin (encoded by the Trf gene) is synthesized primarily in the liver, its function in the liver is largely unknown. Here, we generated hepatocyte-specific Trf knockout mice (Trf-LKO), which are viable and fertile but have impaired erythropoiesis and altered iron metabolism. Moreover, feeding Trf-LKO mice a high-iron diet increased their susceptibility to developing ferroptosis-induced liver fibrosis. Read More

View Article and Full-Text PDF

High Glucose and Liver Fatty Acid Binding Protein Gene Ablation Differentially Impact Whole Body and Liver Phenotype in High-Fat Pair-Fed Mice.

Lipids 2020 07 20;55(4):309-327. Epub 2020 Apr 20.

Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX, 77843, USA.

Ad libitum-fed diets high in fat and carbohydrate (especially fructose) induce weight gain, obesity, and nonalcoholic fatty liver disease (NAFLD) in humans and animal models. However, interpretation is complicated since ad libitum feeding of such diets induces hyperphagia and upregulates expression of liver fatty acid binding protein (L-FABP)-a protein intimately involved in fatty acid and glucose regulation of lipid metabolism. Wild-type (WT) and L-fabp gene ablated (LKO) mice were pair-fed either high-fat diet (HFD) or high-fat/high-glucose diet (HFGD) wherein total carbohydrate was maintained constant but the proportion of glucose was increased at the expense of fructose. Read More

View Article and Full-Text PDF

Loricrin: Past, Present, and Future.

Int J Mol Sci 2020 Mar 25;21(7). Epub 2020 Mar 25.

Department of Dermatology and Charles C. Gates Center for Regenerative Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.

The terminal differentiation of the epidermis is a complex physiological process. During the past few decades, medical genetics has shown that defects in the stratum corneum (SC) permeability barrier cause a myriad of pathological conditions, ranging from common dry skin to lethal ichthyoses. Contrarily, molecular phylogenetics has revealed that amniotes have acquired a specialized form of cytoprotection cornification that provides mechanical resilience to the SC. Read More

View Article and Full-Text PDF

PP2Acα inhibits PFKFB2-induced glycolysis to promote termination of liver regeneration.

Biochem Biophys Res Commun 2020 05 16;526(1):1-7. Epub 2020 Mar 16.

The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China. Electronic address:

The mechanisms underlying the initiation and proliferation of liver regeneration (LR) has been extensively studied using the partial hepatectomy (PHx) model, while little is known about the termination of LR. PP2Acα (protein phosphatase 2 A catalytic subunit α isoform) is the catalytic subunit of protein phosphatase 2 A (PP2A), accounting for most of intracellular serine/threonine phosphatase activity. We have previously observed that termination of LR delayed in PP2Acα liver-specific knockout (LKO) mice after PHx. Read More

View Article and Full-Text PDF

The Long Isoform of Intersectin-1 Has a Role in Learning and Memory.

Front Behav Neurosci 2020 25;14:24. Epub 2020 Feb 25.

Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.

Down syndrome is caused by partial or total trisomy of chromosome 21 and is characterized by intellectual disability and other disorders. Although it is difficult to determine which of the genes over-expressed on the supernumerary chromosome contribute to a specific abnormality, one approach is to study each gene in isolation. This can be accomplished either by using an over-expression model to study increased gene dosage or a gene-deficiency model to study the biological function of the gene. Read More

View Article and Full-Text PDF
February 2020