Regulation of lipogenesis by toll like receptor pathway: effect on stearyl-CoA Desaturase-1

Abstract

Inflammation is commonly observed in many chronic diseases including metabolic disorders, cardiovascular diseases, cancer and autoimmune diseases which are often associated with aging. Senior patients are often taking multiple drugs to controlling these diseases, and population ageing drastically increases the medical most of these diseases. To reduce such medical burden and improve patient compliance, one of the concepts to develop drugs with multi-target. As inflammation is one of the common pathophysiological factors of these diseases, anti-inflammatory drugs seem to be the drug of choice. Unfortunately, although genetic modified animal model and association studies in human demonstrates positive results, the clinical evidence showing beneficial effect of anti-inflammatory drugs in these chronic diseases is controversial. Many of the positive animal studies have focused the role of toll-like receptor (TLR), a classic pathway of innate immunity, in these diseases. In spite of its immune-originality, many cell types other than immune cells express TLR. Evidence of these positive animal studies only demonstrated the TLR effect mediated by the immune cells, and the function in non-immune cells has largely been ignored. Whether this missing area explains the limited effect of anti-inflammatory drug in these diseases shown in clinical study is noteworthy to be explored. In this project, we used a different angle to study the role of TLR pathway in metabolic diseases. Despite that many studies showed the harmful effect elicited by activation of TLR, our data demonstrated that when we genetic deleted one of the downstream cytosolic branches of TLR pathway, TRIF in mice, they displayed a worsened metabolic phenotype under a high fat diet. Hepatic steatosis and elevated fasting blood glucose were present in these TRIF knockout mice. The increased hepatic accumulation of lipid was due to the abnormal upregulation of lipogenesis pathway in hepatocytes. We further showed that activation of TRIF pathway can inhibit the critical lipogenic protein, stearyl-CoA desaturase -1 (SCD-1) in hepatocytes. It appeared that SCD-1 was a direct target of the downstream transcription factor, interferon regulatory factor-3 (IRF3) which is activated through TRIF pathway. These results highly suggested an unconventional effect of TLR pathway in non-immune cells. This study gave us a new understanding of the role and function of TLR/TRIF pathway in non-immune cells during metabolism, thus a different angle to design a more effective therapeutic strategy in treating multiple chronic diseases including metabolic diseases and their fatal complications.