MBOAT7-driven lysophosphatidylinositol acylation in adipocytes contributes to systemic glucose homeostasis.

We previously demonstrated that antisense oligonucleotide-mediated knockdown of Mboat7, the gene encoding membrane bound O-acyltransferase 7, in the liver and adipose tissue of mice promoted high fat diet-induced hepatic steatosis, hyperinsulinemia, and systemic insulin resistance. Thereafter, other groups showed that hepatocyte-specific genetic deletion of Mboat7 promoted striking fatty liver and NAFLD progression in mice but does not alter insulin sensitivity, suggesting the potential for cell autonomous roles. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. We generated Mboat7 floxed mice and created hepatocyte- and adipocyte-specific Mboat7 knockout mice using Cre-recombinase mice under the control of the albumin and adiponectin promoter, respectively. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. The expression of Mboat7 in white adipose tissue closely correlates with diet-induced obesity across a panel of ∼100 inbred strains of mice fed a high fat/high sucrose diet. Moreover, we found that adipocyte-specific genetic deletion of Mboat7 is sufficient to promote hyperinsulinemia, systemic insulin resistance, and mild fatty liver. Unlike in the liver, where Mboat7 plays a relatively minor role in maintaining arachidonic acid-containing PI pools, Mboat7 is the major source of arachidonic acid-containing PI pools in adipose tissue. Our data demonstrate that MBOAT7 is a critical regulator of adipose tissue PI homeostasis, and adipocyte MBOAT7-driven PI biosynthesis is closely linked to hyperinsulinemia and insulin resistance in mice.

The nonvesicular sterol transporter Aster-C plays a minor role in whole body cholesterol balance.

Introduction: The Aster-C protein (encoded by the Gramd1c gene) is an endoplasmic reticulum (ER) resident protein that has been reported to transport cholesterol from the plasma membrane to the ER. Although there is a clear role for the closely-related Aster-B protein in cholesterol transport and downstream esterification in the adrenal gland, the specific role for Aster-C in cholesterol homeostasis is not well understood. Here, we have examined whole body cholesterol balance in mice globally lacking Aster-C under low or high dietary cholesterol conditions. Method: Age-matched Gramd1c +/+ and Gramd1c -/- mice were fed either low (0.02%, wt/wt) or high (0.2%, wt/wt) dietarycholesterol and levels of sterol-derived metabolites were assessed in the feces, liver, and plasma. Results: Compared to wild type controls (Gramd1c +/+) mice, mice lackingGramd1c (Gramd1c -/-) have no significant alterations in fecal, liver, or plasma cholesterol. Given the potential role for Aster C in modulating cholesterol metabolism in diverse tissues, we quantified levels of cholesterol metabolites such as bile acids, oxysterols, and steroid hormones. Compared to Gramd1c +/+ controls, Gramd1c -/- mice had modestly reduced levels of select bile acid species and elevated cortisol levels, only under low dietary cholesterol conditions. However, the vast majority of bile acids, oxysterols, and steroid hormones were unaltered in Gramd1c -/- mice. Bulk RNA sequencing in the liver showed that Gramd1c -/- mice did not exhibit alterations in sterol-sensitive genes, but instead showed altered expression of genes in major urinary protein and cytochrome P450 (CYP) families only under low dietary cholesterol conditions. Discussion: Collectively, these data indicate nominal effects of Aster-C on whole body cholesterol transport and metabolism under divergent dietary cholesterol conditions. These results strongly suggest that Aster-C alone is not sufficient to control whole body cholesterol balance, but can modestly impact circulating cortisol and bile acid levels when dietary cholesterol is limited.

Biomechanical evaluation of unilateral subcondylar fracture of the mandible on the varying materials: A finite element analysis.

Fixation materials used in the surgical treatment of subcondylar fractures contribute to successful clinical outcomes. In this study, we simulated the mechanical properties of four fixation materials [titanium (Ti), magnesium alloy (Mg alloy), poly-L-lactic acid (PLLA), and hydroxyapatite/poly-L-lactide (HA-PLLA)] in a finite-element analysis model of subcondylar fracture. Two four-hole plates were fixed on the anterior and posterior surfaces of the subcondyle of the mandible. In the simulation model of a subcondylar fracture, we evaluated the stress distribution and mechanical deformation of fixation materials. The stress distribution conspicuously appeared on the condylar neck of the non-fractured side and the center of the anterior plate for all materials. More stress distribution to the biologic component appeared with HA-PLLA than with Ti or Mg alloy, but its effects were less prominent than that of PLLA. The largest deformation was observed with PLLA, followed by HA-PLLA, Mg alloy, and Ti. The results of the present study imply the clinical potential of the HA-PLLA fixation material for open reduction of subcondylar fractures.

The Stability of Hydroxyapatite/Poly-L-Lactide Fixation for Unilateral Angle Fracture of the Mandible Assessed Using a Finite Element Analysis Model.

Recently, a hydroxyapatite particle/poly-L-lactide (HA-PLLA) composite device was introduced as an alternative to previous fixation systems. In this study, we used finite element analysis to simulate peak von Mises stress (PVMS) and deformation of bone plates and screws with the following four materials-Ti, Mg alloy, PLLA, and HA-PLLA-at a unilateral mandibular fracture. A three-dimensional virtual mandibular model was constructed, and the fracture surface was designed to run from the left mandibular angle. Masticatory loading was applied on the right first molars. Stress was concentrated at the upper part and the neck of the screw. The largest PVMS was observed for Ti; that was followed by Mg alloy, HA-PLLA, and PLLA. The largest deformation was observed for PLLA; next was HA-PLLA, then Mg alloy, and finally Ti. We could rank relative superiority in terms of mechanical properties. The HA-PLLA screw and mini-plate deformed less than 0.15 mm until 300 N. Thus, we can expect good bone healing with usual masticatory loading six weeks postoperatively. HA-PLLA is more frequently indicated clinically than PLLA owing to less deformation. If the quality of HA-PLLA fixation is improved, it could be widely utilized in facial bone trauma or craniofacial surgery.

Diagnostic index of 3D osteoarthritic changes in TMJ condylar morphology.

The aim of this study was to investigate imaging statistical approaches for classifying 3D osteoarthritic morphological variations among 169 Temporomandibular Joint (TMJ) condyles. Cone beam Computed Tomography (CBCT) scans were acquired from 69 patients with long-term TMJ Osteoarthritis (OA) (39.1 ± 15.7 years), 15 patients at initial diagnosis of OA (44.9 ± 14.8 years) and 7 healthy controls (43 ± 12.4 years). 3D surface models of the condyles were constructed and Shape Correspondence was used to establish correspondent points on each model. The statistical framework included a multivariate analysis of covariance (MANCOVA) and Direction-Projection- Permutation (DiProPerm) for testing statistical significance of the differences between healthy control and the OA group determined by clinical and radiographic diagnoses. Unsupervised classification using hierarchical agglomerative clustering (HAC) was then conducted. Condylar morphology in OA and healthy subjects varied widely. Compared with healthy controls, OA average condyle was statistically significantly smaller in all dimensions except its anterior surface. Significant flattening of the lateral pole was noticed at initial diagnosis (p < 0.05). It was observed areas of 3.88 mm bone resorption at the superior surface and 3.10 mm bone apposition at the anterior aspect of the long-term OA average model. 1000 permutation statistics of DiProPerm supported a significant difference between the healthy control group and OA group (t = 6.7, empirical p-value = 0.001). Clinically meaningful unsupervised classification of TMJ condylar morphology determined a preliminary diagnostic index of 3D osteoarthritic changes, which may be the first step towards a more targeted diagnosis of this condition.

Diagnostic index of three-dimensional osteoarthritic changes in temporomandibular joint condylar morphology.

This study aimed to investigate imaging statistical approaches for classifying three-dimensional (3-D) osteoarthritic morphological variations among 169 temporomandibular joint (TMJ) condyles. Cone-beam computed tomography scans were acquired from 69 subjects with long-term TMJ osteoarthritis (OA), 15 subjects at initial diagnosis of OA, and 7 healthy controls. Three-dimensional surface models of the condyles were constructed and SPHARM-PDM established correspondent points on each model. Multivariate analysis of covariance and direction-projection-permutation (DiProPerm) were used for testing statistical significance of the differences between the groups determined by clinical and radiographic diagnoses. Unsupervised classification using hierarchical agglomerative clustering was then conducted. Compared with healthy controls, OA average condyle was significantly smaller in all dimensions except its anterior surface. Significant flattening of the lateral pole was noticed at initial diagnosis. We observed areas of 3.88-mm bone resorption at the superior surface and 3.10-mm bone apposition at the anterior aspect of the long-term OA average model. DiProPerm supported a significant difference between the healthy control and OA group ([Formula: see text]). Clinically meaningful unsupervised classification of TMJ condylar morphology determined a preliminary diagnostic index of 3-D osteoarthritic changes, which may be the first step towards a more targeted diagnosis of this condition.