Khalifeh-Soltani A.,University of California at San Francisco |
McKleroy W.,University of California at San Francisco |
Sakuma S.,University of California at San Francisco |
Cheung Y.Y.,University of California at San Francisco |
And 6 more authors.
Nature Medicine | Year: 2014
Fatty acids are integral mediators of energy storage, membrane formation and cell signaling. The pathways that orchestrate uptake of fatty acids remain incompletely understood. Expression of the integrin ligand Mfge8 is increased in human obesity and in mice on a high-fat diet, but its role in obesity is unknown. We show here that Mfge8 promotes the absorption of dietary triglycerides and the cellular uptake of fatty acid and that Mfge8-deficient (Mfge8-/-) mice are protected from diet-induced obesity, steatohepatitis and insulin resistance. Mechanistically, we found that Mfge8 coordinates fatty acid uptake through α v β 3 integrin-and α v β 5 integrin-dependent phosphorylation of Akt by phosphatidylinositide-3 kinase and mTOR complex 2, leading to translocation of Cd36 and Fatp1 from cytoplasmic vesicles to the cell surface. Collectively, our results imply a role for Mfge8 in regulating the absorption and storage of dietary fats, as well as in the development of obesity and its complications. © 2014 Nature America, Inc.
Miller B.F.,Colorado State University |
Robinson M.M.,Colorado State University |
Bruss M.D.,University of California at Berkeley |
Hellerstein M.,University of California at Berkeley |
And 2 more authors.
Aging Cell | Year: 2012
It is proposed that caloric restriction (CR) increases mitochondrial biogenesis. However, it is not clear why CR increases an energetically costly biosynthetic process. We hypothesized that 40% CR would decrease mitochondrial protein synthesis and would be regulated by translational rather than transcriptional mechanisms. We assessed cumulative mitochondrial protein synthesis over 6weeks and its transcriptional and translational regulation in the liver, heart, and skeletal muscle of young (6month), middle (12month), and old (24month) male B6D2F1 mice that were lifelong CR or ad lib (AL) controls. Mitochondrial protein synthesis was not different between AL and CR (fractional synthesis over 6weeks (range): liver, 91-100%; heart, 74-85%; skeletal muscle, 53-72%) despite a decreased cellular proliferation in liver and heart with CR. With CR, there was an increase in AMP-activated protein kinase phosphorylation/total (P:T) in heart and liver, and an increase in peroxisome proliferator-activated receptor gamma coactivator 1-α mRNA in all tissues, but not protein. Ribosomal protein S6 was decreased with CR. In conclusion, CR maintained mitochondrial protein synthesis while decreasing cellular proliferation during a time of energetic stress, which is consistent with the concept that CR increases somatic maintenance. Alternative mechanisms to global translation initiation may be responsible for selective translation of mitochondrial proteins. © 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
Kinemed Inc. | Date: 2012-04-30
Hydrocarbon stapling of apolipoprotein mimetic peptides increases the helicity of the peptides, enhances their ability to promote cholesterol efflux by multiple mechanisms and makes them resistant to proteolysis. Hydrocarbon stapled amphipathic helical peptides are useful in the treatment of cardiovascular diseases and other disorders.
Glaxosmithkline and Kinemed Inc. | Date: 2012-12-06
The present invention is based on the finding that enrichment of D3-creatinine in a urine sample following oral administration of a single defined dose of D3-creatine can be used to calculate total-body creatine pool size and total body skeletal muscle mass in a subject. The invention further encompasses methods for detecting creatinine and D3-creatinine in a single sample. The methods of the invention find use, inter alia, in diagnosing disorders related to skeletal muscle mass, and in screening potential therapeutic agents to determine their effects on muscle mass.
Kinemed Inc. and The United States Of America | Date: 2015-07-31
The present invention relates to peptide-phospholipid formulations, methods of generating these formulations and methods of administering these formulations for treatment. The present disclosure also provides methods for increasing cholesterol efflux, inducing anti-atherosclerotic activity, increasing pre- HDL, inducing anti-inflammatory activity, inhibiting cytokine release (including cytokines TNF-, IL-1, and/or IL-6 or a combination thereof) and increasing cholesterol mobilization and/or esterification by administering the peptide-phospholipid formulations disclosed.