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1.
Nutrients ; 14(12)2022 Jun 15.
Article in English | MEDLINE | ID: mdl-35745205

ABSTRACT

The mechanisms connecting obesity with type 2 diabetes, insulin resistance, nonalcoholic fatty liver disease, and cardiovascular diseases remain incompletely understood. The function of MAPK phosphatase-2 (MKP-2), a type 1 dual-specific phosphatase (DUSP) in whole-body metabolism, and how this contributes to the development of diet-induced obesity, type 2 diabetes (T2D), and insulin resistance is largely unknown. We investigated the physiological contribution of MKP-2 in whole-body metabolism and whether MKP-2 is altered in obesity and human fatty liver disease using MKP-2 knockout mice models and human liver tissue derived from fatty liver disease patients. We demonstrate that, for the first time, MKP-2 expression was upregulated in liver tissue in humans with obesity and fatty liver disease and in insulin-responsive tissues in mice with obesity. MKP-2-deficient mice have enhanced p38 MAPK, JNK, and ERK activities in insulin-responsive tissues compared with wild-type mice. MKP-2 deficiency in mice protects against diet-induced obesity and hepatic steatosis and was accompanied by improved glucose homeostasis and insulin sensitivity. Mkp-2-/- mice are resistant to diet-induced obesity owing to reduced food intake and associated lower respiratory exchange ratio. This was associated with enhanced circulating insulin-like growth factor-1 (IGF-1) and stromal cell-derived factor 1 (SDF-1) levels in Mkp-2-/- mice. PTEN, a negative regulator of Akt, was downregulated in livers of Mkp-2-/- mice, resulting in enhanced Akt activity consistent with increased insulin sensitivity. These studies identify a novel role for MKP-2 in the regulation of systemic metabolism and pathophysiology of obesity-induced insulin resistance and fatty liver disease.


Subject(s)
Diabetes Mellitus, Type 2 , Fatty Liver , Insulin Resistance , Animals , Diabetes Mellitus, Type 2/metabolism , Dual Specificity Phosphatase 1/metabolism , Dual-Specificity Phosphatases , Fatty Liver/metabolism , Humans , Insulin/metabolism , Liver/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mitogen-Activated Protein Kinase Phosphatases , Obesity/metabolism , Protein Tyrosine Phosphatases , Proto-Oncogene Proteins c-akt/metabolism , Up-Regulation
2.
Membranes (Basel) ; 12(4)2022 Apr 09.
Article in English | MEDLINE | ID: mdl-35448380

ABSTRACT

Obesity has reached global epidemic proportions and it affects the development of insulin resistance, type 2 diabetes, fatty liver disease and other metabolic diseases. Membrane lipids are important structural and signaling components of the cell membrane. Recent studies highlight their importance in lipid homeostasis and are implicated in the pathogenesis of fatty liver disease. Here, we discuss the numerous membrane lipid species and their metabolites including, phospholipids, sphingolipids and cholesterol, and how dysregulation of their composition and physiology contribute to the development of fatty liver disease. The development of new genetic and pharmacological mouse models has shed light on the role of lipid species on various mechanisms/pathways; these lipids impact many aspects of the pathophysiology of fatty liver disease and could potentially be targeted for the treatment of fatty liver disease.

3.
Lab Invest ; 100(5): 790, 2020 May.
Article in English | MEDLINE | ID: mdl-31942004

ABSTRACT

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

4.
Lab Invest ; 99(12): 1850-1860, 2019 12.
Article in English | MEDLINE | ID: mdl-31467425

ABSTRACT

We examined bone formation and turnover in high-density lipoprotein (HDL) receptor, scavenger receptor type I (Scarb1), knockout animals relative to wild-type (WT) controls. Scarb1-/- animals have elevated serum adrenocorticotropic hormone (ACTH) due to the role of Scarb1 in glucocorticoid production, which might cause increased bone mass. However, this was not observed: Scarb1-/- mice, with ACTH, over 1000 pg/ml relative to wild-type ACTH ~ 25 pg/ml, bone of the knockout animals was osteopenic relative to the wild type at 16 weeks, including bone volume/total volume and trabecular thickness. Other serum parameters of WT and Scarb1-/- animals in cortisol or calcium were unaffected, although Scarb1-/- animals had significantly elevated PTH and decreased phosphate. Osteoblast and osteoclast-related mRNAs extracted from bone were greatly decreased at 8 or 16 weeks. Importantly, in normal ACTH, osteogenic differentiation in vitro from mesenchymal stem cells showed reduced alkaline phosphatase and mineralization. In Scarb1-/- cells relative to WT, mRNAs for RunX2, alkaline phosphatase, type I collagen, and osteocalcin were reduced 40-90%, all p < 0.01, indicating a role of Scarb1 in osteoblast differentiation independent of ACTH. Additionally, in vitro osteoblast differentiation at variable ACTH in WT cells confirmed ACTH increasing bone differentiation, mineralization, alkaline phosphatase, and osteocalcin mRNA at 0-10 nM ACTH, but reduced bone differentiation at 100-1000 nM ACTH. Overall Scarb1-/- animals show inhibited bone formation with age. This may be a mixed effect on direct bone formation and of very high ACTH. Further, this work shows that both ACTH concentration and the HDL receptor Scarb1 play important independent roles in osteoblast differentiation.


Subject(s)
Adrenocorticotropic Hormone/blood , Cell Differentiation , Osteoblasts , Osteogenesis , Scavenger Receptors, Class B/physiology , Animals , Bone Density , Bone Remodeling , Female , Male , Mice , Mice, Knockout , Osteoclasts , Primary Cell Culture
5.
Mol Genet Metab ; 125(3): 193-199, 2018 11.
Article in English | MEDLINE | ID: mdl-30201326

ABSTRACT

Osteopenia is observed in some patients affected by phenylalanine hydroxylase (PAH) deficient phenylketonuria (PKU). Bone density studies, in diverse PKU patient cohorts, have demonstrated bone disease is neither fully penetrant nor uniform in bone density loss. Biochemical assessment has generated a muddled perspective regarding mechanisms of the PKU bone phenotype where the participation of hyperphenylalaninemia remains unresolved. Osteopenia is realized in the Pahenu2 mouse model of classical PKU; although, characterization is incomplete. We characterized the Pahenu2 bone phenotype and assessed the effect of hyperphenylalaninemia on bone differentiation. Employing Pahenu2 and control animals, cytology, static and dynamic histomorphometry, and biochemistry were applied to further characterize the bone phenotype. These investigations demonstrate Pahenu2 bone density is decreased 33% relative to C57BL/6; bone volume/total volume was similarly decreased; trabecular thickness was unchanged while increased trabecular spacing was observed. Dynamic histomorphometry demonstrated a 25% decrease in mineral apposition. Biochemically, control and PKU animals have similar plasma cortisol, adrenocorticotropic hormone, and 25-hydroxyvitamin D. PKU animals show moderately increased plasma parathyroid hormone while plasma calcium and phosphate are reduced. These data are consistent with a mineralization defect. The effect of hyperphenylalaninemia on bone maturation was assessed in vitro employing bone-derived mesenchymal stem cells (MSCs) and their differentiation into bone. Using standard culture conditions, PAH deficient MSCs differentiate into bone as assessed by in situ alkaline phosphatase activity and mineral staining. However, PAH deficient MSCs cultured in 1200 µM PHE (metric defining classical PKU) show significantly reduced mineralization. These data are the first biological evidence demonstrating a negative impact of hyperphenylalaninemia upon bone maturation. In PAH deficient MSCs, expression of Col1A1 and Rankl are suppressed by hyperphenylalaninemia consistent with reduced bone formation and bone turnover. Osteopenia is intrinsic to PKU pathology in untreated Pahenu2 animals and our data suggests PHE toxicity participates by inhibiting mineralization in the course of MSC bone differentiation.


Subject(s)
Collagen Type I/genetics , Mesenchymal Stem Cells/metabolism , Phenylalanine Hydroxylase/genetics , Phenylketonurias/genetics , RANK Ligand/genetics , Alkaline Phosphatase/genetics , Animals , Bone Density/genetics , Bone Diseases, Metabolic/genetics , Bone Diseases, Metabolic/metabolism , Bone Diseases, Metabolic/pathology , Calcification, Physiologic/genetics , Cell Differentiation/genetics , Collagen Type I, alpha 1 Chain , Disease Models, Animal , Gene Expression Regulation, Developmental/genetics , Humans , Liver/metabolism , Liver/pathology , Mesenchymal Stem Cells/pathology , Mice , Phenylalanine/genetics , Phenylalanine/metabolism , Phenylketonurias/metabolism , Phenylketonurias/pathology , Vitamin D/analogs & derivatives , Vitamin D/genetics , Vitamin D/metabolism
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