Medical Protein Science
The Medical Protein Science unit run by Dr Jens Lagerstedt and his research team investigates two areas of research with impact on human lipid and glucose transport and metabolism: ApoA-I biology in health and disease and Zinc transporters and diabetes. The research carried out covers a wide spectrum of approaches and ranges from molecular protein structure/function analyses to integrative metabolism studies.
ApoA-I biology in health and disease
The team has investigated different aspects of the apoA-I protein of the high-density lipoprotein (HDL) particles. ApoA-I/HDL transports cholesterol and other lipids in blood circulation, which is critical for balanced cholesterol levels in, e.g., the vascular wall (where too much cholesterol may lead to atherosclerosis).
Based on biophysical approaches such as electron paramagnetic resonance spectroscopy, the early studies carried by Lagerstedt and colleagues largely focused on protein structure, and structure transitions in the lipid-loading process of apoA-I in the formation of nascent HDL. These studies have led to a detailed map of the structures in the two states (lipid-free and lipid-bound). In addition to studies on the native apoA-I protein, significant emphasis has also been placed on explaining the structure biology and function of amyloidogenic apoA-I variants that lead to abnormal aggregation in tissues (e.g., liver, skin, heart, larynx). While being a rare disease, the aggregation of the amyloidogenic apoA-I protein in human carriers may severely impact the function of the affected organ. The team aim to understand the fundamental molecular and cellular principles of how the protein alterations affect the target organs.
ApoA-I/HDL is critical for lipid transport and metabolism. Recently, apoA-I has also been shown to provide glucose control with a potential impact on the etiology and treatment of diabetes. To understand the specific effects of apoA-I on glucose control, the Lagerstedt team examines how tissues such as skeletal muscle, heart, fat and pancreatic islets are affected. Lagerstedt and colleagues have also identified the bioactive peptide of the apoA-I protein that provides the beneficial effects on blood glucose. This finding is currently in preclinical testing as a potential diabetes drug.
Zinc transporters and diabetes
Zinc-ions are important for the storage of the insulin peptide in intracellular vesicles in pancreatic beta cells. The zinc is transported to the interior of the vesicles by membrane protein ZnT8 (encoded by the SLC30A8 gene). Polymorphisms in SLC30A8 (R325W substitution in ZnT8 and also loss-of-function variants) are linked to risk of type 2 diabetes. Modulation of the ZnT8 function is therefore a tangible target for diabetes treatment. With the goal to understand the basic science, and to explore the innovation potential, the Lagerstedt team studies the cellular, molecular and structural biology of the ZnT8 protein variants and how this affects pancreatic islet function.
Domingo-Espin J, Lindahl M, Nilsson-Wolanin O, Cushman SW, Stenkula KG, and Lagerstedt JO Dual actions of apolipoprotein A-I on glucose-stimulated insulin secretion and insulin-independent peripheral tissue glucose uptake lead to increased heart and skeletal muscle glucose disposal. Diabetes, 2016; accepted for publication.
Skärstrand H, Krupinska E, Haataja T, Vaziri-Sani F, Lagerstedt JO and Lernmark Å, ZnT8 autoantibody epitope specificity and affinity examined with recombinant ZnT8 variant proteins in specific ZnT8R and ZnT8W autoantibody positive type 1 diabetes patients, Clinical and Experimental Immunology; 2015; 179:220-229.
Petrlova J, Bhattacherjee A, Boomsma W, Wallin S, Lagerstedt JO and Irbäck A Conformational and aggregation properties of the 1–93 fragment of apolipoprotein A‐I, Protein Science, 2014; 23:1559-15571
Stenkula KG, Lindahl M, Petrlova J, Dalla-Riva J, Göransson O, Cushman SW, Krupinska E, Jones, HA and Lagerstedt JO Single injections of apoA-I acutely improve in vivo glucose tolerance in insulin-resistant mice, Diabetologia, 2014; 57:797-800.
Dalla-Riva J, Stenkula KG, Petrlova J and Lagerstedt JO Discoidal HDL and apoA-I-derived peptides improve glucose uptake in skeletal muscle, Journal of Lipid Research, 2013; 54:1275-1282.
Oda MN, Budamagunta M, Borja M, Petrlova J, Voss JC, and Lagerstedt JO The secondary structure of apoA-I on 9.6 nm rHDL determined by EPR spectroscopy, FEBS Journal, 2013; 280:3416-3424
Petrlova J, Cochran M, Duong T, Axelsson A, Mörgelin M, Roberts LM, and Lagerstedt JO The fibrillogenic Leu178His variant of apolipoprotein A-I forms helical fibrils, Journal of Lipid Research, 2012; 53:390-398.