The Lipolysis Stimulated Receptor – A Novel Contender on the Diabetes Arena?

Type 2 Diabetes is among the fastest spreading diseases worldwide. It is characterized by the insensitivity of peripheral organs to insulin. Although several factors such as genetic predisposition, obesity, aging, environmental conditions and life style trigger its development, the intricate mechanisms of insulin resistance remain largely unclear. Therefore, we aimed to identify hormone – dependent regulation of genes involved in the development of hepatic insulin resistance using cDNA microarray technology.

We performed transcriptional profiling of insulin – dependent and counter – regulatory signaling pathways in the livers of fed and fasted wild – type and diabetic mice using a non – redundant mouse library with 20000 ESTs. The data was analyzed using the software tool MCHiPS. We further confirmed the significance of the results by an independent SAM program. On the whole, taking the wild type fed animals as the control group, we found 510, 193 and 386 genes to be regulated in diabetic fasted, diabetic fed and wild type fasted animals respectively. Of these 231, 83 and 109 genes were up – regulated and 279, 110 and 277 genes were down – regulated in the above mentioned conditions respectively.

One of the targets in this experiment turned out to be the potential plasma membrane receptor, LSR (Lipolysis Stimulated Lipoprotein Receptor) also known as Lisch7. This receptor was found to be significantly down – regulated in diabetic mice livers. LSR, upon activation by free fatty acids is known to be involved in the clearance of triglyceride – rich lipoproteins and chylomicron remnants. We observed a similar down – regulation of LSR by quantitative RT – PCR in two other independent mouse experiments where animals were fed and fasted in the same manner. Moreover, we also saw a down – regulation of LSR in High – Fat Diet fed mice but not in a mouse model for type 1 Diabetes. In order to characterize the functional role of LSR in diabetic liver metabolism we have developed adenoviral siRNAs that will generate a liver – specific deficiency of LSR in mice.

We expect these studies to establish the presence of a novel player in the development of insulin resistance and consequently type 2 Diabetes.