LECT2 Deletion Exacerbates Liver Steatosis and Macrophage Infiltration in a Male Mouse Model of LPS-mediated NASH.

Leukocyte cell-derived chemotaxin 2 (LECT2) is a protein initially isolated as a neutrophil chemotactic factor. We previously found that LECT2 is an obesity-associated hepatokine that senses liver fat and induces skeletal muscle insulin resistance. In addition, hepatocyte-derived LECT2 activates macrophage proinflammatory activity by reinforcing the lipopolysaccharide (LPS)-induced c-Jun N-terminal kinase signaling.

Diabetes Accelerates Steatohepatitis in Mice: Liver Pathology and Single-Cell Gene Expression Signatures.

Glucose lowering independently reduces liver fibrosis in human nonalcoholic fatty liver disease. This study investigated the impact of diabetes on steatohepatitis and established a novel mouse model for diabetic steatohepatitis. Male C57BL/6J mice were fed a 60% high-fat diet (HFD) and injected with carbon tetrachloride (CCl) and streptozotocin (STZ) to induce diabetes.

PAC1 Deficiency Protects Obese Male Mice From Immobilization-Induced Muscle Atrophy by Suppressing FoxO-Atrogene Axis.

Muscle atrophy is the cause and consequence of obesity. Proteasome dysfunction mediates obesity-induced endoplasmic reticulum (ER) stress and insulin resistance in the liver and adipose tissues. However, obesity-associated regulation of proteasome function and its role in the skeletal muscles remains underinvestigated.

Selenoprotein P deficiency protects against immobilization-induced muscle atrophy by suppressing atrophy-related E3 ubiquitin ligases.

The quality of skeletal muscle is maintained by a balance between protein biosynthesis and degradation. Disruption in this balance results in sarcopenia. However, its underlying mechanisms remain underinvestigated.

Insulin Suppresses Ubiquitination via the Deubiquitinating Enzyme Ubiquitin-Specific Protease 14, Independent of Proteasome Activity in H4IIEC3 Hepatocytes.

Ubiquitin-proteasome dysfunction contributes to obesity-related metabolic disorders, such as diabetes and fatty liver disease. However, the regulation of ubiquitin-proteasome activity by insulin remains to be elucidated. Here, we show that prolonged insulin stimulation activates proteasome function even though it reduces the ubiquitinated proteins in H4IIEC3 hepatocytes.

Cyclosporine A Downregulates Selenoprotein P Expression via a Signal Transducer and Activator of Transcription 3-Forkhead Box Protein O1 Pathway in Hepatocytes In Vitro.

Cyclosporine A (CsA) is an immunosuppressant applied worldwide for preventing graft rejection and autoimmune diseases. However, CsA elevates oxidative stress, which can lead to liver injuries. The present study aimed to clarify the mechanisms underlying the CsA-mediated oxidative stress.

Leukocyte cell-derived chemotaxin 2 is an antiviral regulator acting through the proto-oncogene MET.

Retinoic acid-inducible gene (RIG)-I is an essential innate immune sensor that recognises pathogen RNAs and induces interferon (IFN) production. However, little is known about how host proteins regulate RIG-I activation. Here, we show that leukocyte cell-derived chemotaxin 2 (LECT2), a hepatokine and ligand of the MET receptor tyrosine kinase is an antiviral regulator that promotes the RIG-I-mediated innate immune response.

Lauric acid impairs insulin-induced Akt phosphorylation by upregulating SELENOP expression via HNF4α induction.

Selenoprotein P (SeP; encoded by SELENOP in humans, Selenop in rodents) is a hepatokine that is upregulated in the liver of humans with type 2 diabetes. Excess SeP contributes to the onset of insulin resistance and various type 2 diabetes-related complications. We have previously reported that the long-chain saturated fatty acid, palmitic acid, upregulates Selenop expression, whereas the polyunsaturated fatty acids (PUFAs) downregulate it in hepatocytes.

Selenoprotein P-mediated reductive stress impairs cold-induced thermogenesis in brown fat.

Reactive oxygen species (ROS) activate uncoupler protein 1 (UCP1) in brown adipose tissue (BAT) under physiological cold exposure and noradrenaline (NA) stimulation to increase thermogenesis. However, the endogenous regulator of ROS in activated BAT and its role in pathological conditions remain unclear. We show that serum levels of selenoprotein P (SeP; encoded by SELENOP) negatively correlate with BAT activity in humans.

Forkhead box protein O1 (FoxO1) knockdown accelerates the eicosapentaenoic acid (EPA)-mediated Selenop downregulation independently of sterol regulatory element-binding protein-1c (SREBP-1c) in H4IIEC3 hepatocytes.

Selenoprotein P is upregulated in type 2 diabetes, causing insulin and exercise resistance. We have previously reported that eicosapentaenoic acid (EPA) negatively regulates Selenop expression by suppressing Srebf1 in H4IIEC3 hepatocytes. However, EPA downregulated Srebf1 long before downregulating Selenop.

Role of selenoprotein P expression in the function of pancreatic β cells: Prevention of ferroptosis-like cell death and stress-induced nascent granule degradation.

Selenoprotein P (SELENOP) is a major selenium (Se)-containing protein (selenoprotein) in human plasma that is mainly synthesized in the liver. SELENOP transports Se to the cells, while SELENOP synthesized in peripheral tissues is incorporated in a paracrine/autocrine manner to maintain the levels of cellular selenoproteins, called the SELENOP cycle. Pancreatic β cells, responsible for the synthesis and secretion of insulin, are known to express SELENOP.

Effects of eicosapentaenoic acid on serum levels of selenoprotein P and organ-specific insulin sensitivity in humans with dyslipidemia and type 2 diabetes.

Aim: Selenoprotein P (SeP, encoded by SELENOP in humans) is a hepatokine that causes insulin resistance in the liver and skeletal muscle. It was found that polyunsaturated fatty acid eicosapentaenoic acid (EPA) downregulates Selenop expression by inactivating SREBP-1c. The present study aimed to examine the effect of EPA for 12 weeks on circulating SeP levels and insulin sensitivity in humans with type 2 diabetes.

Corrigendum: Alcohol Intake Is Associated With Elevated Serum Levels of Selenium and Selenoprotein P in Humans.

[This corrects the article DOI: 10.3389/fnut.2021.

Osteosarcoma-Derived Small Extracellular Vesicles Enhance Tumor Metastasis and Suppress Osteoclastogenesis by miR-146a-5p.

Osteosarcoma is the most frequent type of primary bone tumor in children and adolescents, thus care for patients with malignant osteosarcoma is strongly required. The roles of small extracellular vesicles (SEVs) in enhancing metastases have been demonstrated in multiple tumors, but they are still poorly understood in osteosarcoma. Hence, this study investigated the effects of SEVs on progression and the tumor microenvironment in mice and patients.

Alcohol Intake Is Associated With Elevated Serum Levels of Selenium and Selenoprotein P in Humans.

Selenoprotein P is a hepatokine with antioxidative properties that eliminate a physiologic burst of reactive oxygen species required for intracellular signal transduction. Serum levels of selenoprotein P are elevated during aging and in people with type 2 diabetes, non-alcoholic fatty liver disease, and hepatitis C. However, how serum levels of full-length selenoprotein P are regulated largely remains unknown, especially in the general population.

LECT2 as a hepatokine links liver steatosis to inflammation via activating tissue macrophages in NASH.

It remains unclear how hepatic steatosis links to inflammation. Leukocyte cell-derived chemotaxin 2 (LECT2) is a hepatokine that senses fat in the liver and is upregulated prior to weight gain. The aim of this study was to investigate the significance of LECT2 in the development of nonalcoholic steatohepatitis (NASH).

Photothermal excitation efficiency enhancement of cantilevers by electron beam deposition of amorphous carbon thin films.

In recent years, the atomic force microscope has proven to be a powerful tool for studying biological systems, mainly for its capability to measure in liquids with nanoscale resolution. Measuring tissues, cells or proteins in their physiological conditions gives us access to valuable information about their real 'in vivo' structure, dynamics and functionality which could then fuel disruptive medical and biological applications. The main problem faced by the atomic force microscope when working in liquid environments is the difficulty to generate clear cantilever resonance spectra, essential for stable operation and for high resolution imaging.

Plasma half-life and tissue distribution of leukocyte cell-derived chemotaxin 2 in mice.

Leukocyte cell-derived chemotaxin 2 (LECT2) is a hepatokine that causes skeletal muscle insulin resistance. The circulating levels of LECT2 are a possible biomarker that can predict weight cycling because they reflect liver fat and precede the onset of weight loss or gain. Herein, to clarify the dynamics of this rapid change in serum LECT2 levels, we investigated the in vivo kinetics of LECT2, including its plasma half-life and tissue distribution, by injecting I-labelled LECT2 into ICR mice and radioactivity tracing.

Induction of Selenoprotein P mRNA during Hepatitis C Virus Infection Inhibits RIG-I-Mediated Antiviral Immunity.

Patients infected with hepatitis C virus (HCV) have an increased risk of developing type 2 diabetes. HCV infection is linked to various liver abnormalities, potentially contributing to this association. We show that HCV infection increases the levels of hepatic selenoprotein P (SeP) mRNA (SEPP1 mRNA) and serum SeP, a hepatokine linked to insulin resistance.

A novel mutation associated with vitamin D-resistant rickets.

X-linked hypophosphatemic rickets (XLH) is the most common form of hereditary rickets. Here, we present a case of XLH associated with a novel mutation in a phosphate-regulating gene with homologies to endopeptidases on the X chromosome (). PCR-direct sequencing revealed a novel mutation in exon 22, NM_000444.

Circulating Concentrations of Insulin Resistance-Associated Hepatokines, Selenoprotein P and Leukocyte Cell-Derived Chemotaxin 2, during an Oral Glucose Tolerance Test in Humans.

A hepatokine is a collective term for liver-derived secretory factors whose previously-unrecognized functions have been recently elucidated. We have rediscovered selenoprotein P (SeP) and leukocyte cell-derived chemotaxin 2 (LECT2) as hepatokines that are involved in the development of insulin resistance and hyperglycemia. The aim of this study was to determine whether and, if so, how oral glucose loading alters the two hepatokines in humans.

p62-mediated autophagy affects nutrition-dependent insulin receptor substrate 1 dynamics in 3T3-L1 preadipocytes.

Aims/introduction: Previous studies have shown that an organism's nutritional status changes the protein levels of insulin receptor substrate 1 (IRS-1) in a tissue-specific manner. Although the mechanisms underlying the regulation of IRS-1 in the nutrient-rich conditions associated with diabetes and insulin resistance have been well studied, those under nutrient-poor conditions remain unknown. The aim of the present study was to investigate how IRS-1 protein levels change depending on the nutritional status of 3T3-L1 preadipocytes.

Eicosapentaenoic acid down-regulates expression of the selenoprotein P gene by inhibiting SREBP-1c protein independently of the AMP-activated protein kinase pathway in H4IIEC3 hepatocytes.

Selenoprotein P (encoded by in humans, in rat), a liver-derived secretory protein, induces resistance to insulin and vascular endothelial growth factor (VEGF) in type 2 diabetes. Suppression of selenoprotein P may provide a novel therapeutic approach to treating type 2 diabetes; however, few drugs inhibiting expression in hepatocytes have been identified. The present findings demonstrate that eicosapentaenoic acid (EPA) suppresses expression by inactivating sterol regulatory element-binding protein-1c (SREBP-1c, encoded by in rat) in H4IIEC3 hepatocytes.

Deficiency of the hepatokine selenoprotein P increases responsiveness to exercise in mice through upregulation of reactive oxygen species and AMP-activated protein kinase in muscle.

Exercise has numerous health-promoting effects in humans; however, individual responsiveness to exercise with regard to endurance or metabolic health differs markedly. This 'exercise resistance' is considered to be congenital, with no evident acquired causative factors. Here we show that the anti-oxidative hepatokine selenoprotein P (SeP) causes exercise resistance through its muscle receptor low-density lipoprotein receptor-related protein 1 (LRP1).