Yuka Matoba

The lack of the C-terminal domain of adipose triglyceride lipase causes neutral lipid storage disease through impaired interactions with lipid droplets

CONTEXT The molecular mechanisms by which triglycerides in lipid droplets (LDs) are synthesized, stored, and degraded need to be elucidated. OBJECTIVE The objectives were to report siblings with neutral lipid storage disease with myopathy (NLSDM) with a novel mutation of adipose triglyceride lipase (ATGL) and determine whether the C-terminal part of ATGL containing the hydrophobic region plays a role in the interaction with LDs. DESIGN AND PATIENTS Skin fibroblasts and peripheral blood leukocytes were obtained from NLSDM patients. In vitro experiments were performed with fibroblasts and COS7 cells. MAIN OUTCOME MEASURES Transfection studies were used to assess the effects of various recombinant ATGL proteins on lipase activities and lipid contents. Fluorescence microscopy were used for determination of intracellular distribution of ATGL proteins. RESULTS The direct sequence of ATGL cDNA reveals that a patient is a homozygote for the 4-bp deletion, leading to a premature stop codon and causes the lack of the C terminus of the protein including the hydrophobic domain. Overexpressed control ATGL in NLSDM fibroblasts was found around the rims of LDs and caused significantly reduced cellular lipid accumulation. In contrast, NLSDM ATGL was homogeneously located in the cytoplasm despite the presence of LDs and had almost no effect on LD degradation despite its similar lipase activity. A series of C-terminal truncated ATGLs without the intact hydrophobic domain failed to localize around and degrade LDs. CONCLUSIONS These findings indicate that the domain including the hydrophobic region of ATGL was essential for association with LDs.

Impact of metabolic syndrome on the progression of intima-media thickening in Japanese—A follow-up study

The presence of metabolic syndrome (MetS) and its individual components is related to an increased IMT. MetS and increasing numbers of individual MetS components predicted future progression of IMT. Improvement of MetS was related to smaller increases in IMT, especially in females. These findings may suggest a benefit of intervention for MetS, which needs to be confirmed by prospective studies.

Waist Circumference for the Clinical Diagnosis of Metabolic Syndrome in the Japanese Population: Optimal Cut-Point to Predict Early Arteriosclerosis

Metabolic syndrome (MetS) has been proposed as a syndrome in an individual with clustered metabolic dysfunction including increased abdominal adiposity, raised blood pressure, raised triglyceride and/or reduced HDL cholesterol and raised fasting plasma glucose. At the time of writing, several definitions for clinical diagnosis of MetS have been proposed by different organizations. Clinical methods to evaluate visceral adiposity include abdominal computed tomography, body mass index, and waist and hip circumference; in which waist circumference is the most available, but is highly dependent on the ethnicity. Current MetS definitions include waist circumference as a surrogate marker for visceral adiposity and adapt cut-points of waist circumference for each ethnic group to optimize their predictive values. For Asians, the International Diabetes Federation (IDF), the American Heart Association and the National Heart, Lung and Blood Institute have provided the waist cut-points as 90 cm for men and 80 cm for women as recommended by the World Health Organization. By contrast, the previous IDF definition and the Japanese Committee for the Diagnostic Criteria of Metabolic Syndrome adopted waist cut-points of 85 cm for Japanese men and 90 cm for Japanese women which were derived from the cut-points of visceral fat area by computed tomography to identify clustered risk factors. After the MetS definitions were published, waist cut-points for the Japanese population have been re-evaluated in several studies. Our recent studies obtained optimal waist cut-points (87 cm for men and 80 cm for women) from the relation between waist circumference and risk factor clustering in a Japanese population. It showed superior sensitivity and specificity to the conventional IDF (90 cm), which is also the cut-points for Japanese women (90 cm), to predict intima-media thickening; it also agreed with the revised IDF definition (80 cm) for women. These studies suggest that the waist cut-points of 90 cm for men and 80 cm for women are relevant for Japanese population to define MetS with a short-term risk of development of atherosclerosis. Further studies with larger population and longer follow-up period may validate these waist cut-points for the clinical diagnosis of MetS with a substantial risk of cardiovascular events and/or onset of type 2 diabetes.

Recombinant human growth hormone replacement in a Japanese man with a novel PROP1 gene mutation (R112X).

Congenital combined pituitary hormone deficiency (CPHD) is associated with deficiencies of anterior pituitary hormones. PROP1 gene mutations are often responsible for CPHD, but few such cases have been reported in Japan. This study describes a 37-year-old Japanese man with CPHD, treated with hydrocortisone, testosterone, and L-thyroxine, who was evaluated for adult growth hormone deficiency (GHD). Gene analysis revealed a previously unknown PROP1 mutation (R112X). After 10 months of recombinant human growth hormone (rhGH) administration, cortisol and urinary free cortisol levels were significantly lower than before therapy. This case underscores the importance of reassessing hypothalamic-pituitary-adrenal axis function in GHD patients, especially those with a PROP1 mutation, during rhGH therapy.