What’s Tipping the Scale: Sex Differences in Liver Fibrosis [online video]
Original Publication Date
A novel anti-fibrotic role of Sphingosine 1-Phosphate in liver underlies female specific protection from fibrosis
Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common liver disorder with an estimated economic impact of $292 billion in United States alone. NAFLD comprises a range of symptoms including inflammation, fibrosis, cirrhosis, liver carcinoma, and liver failure. Fibrosis is amongst the earliest stages of liver damage and can be targeted for therapeutic approaches. Pre-menopausal women have been known to be protected from fibrosis and mechanisms causing this sexual dimorphism are not fully understood. Therefore, the ultimate goal of this study is to understand the underlying mechanism of protection from fibrosis in order to further the development of a novel therapeutic target for NAFLD.
Sphingosine Kinase-1 (SphK1) knockout mice were previously created in our lab which showed that Sphingosine 1-Phospohate (S1P) is one of the factors regulating fibrosis in NAFLD. Therefore, a hepatocyte specific SK1 murine knockout model (SK1HepKO) was created. SK1HepKO mice showed partial protection from inflammation on high fat diet. But, interestingly only male mice were protected from fibrogenesis whereas female mice showed a 10-fold increase in collagen expression. In-vitro studies showed an increase in S1P secretion in cultured female hepatocytes upon estrogen treatment. Furthermore, TGFβ activated human hepatic stellate cells showed a significant decrease in collagen message and protein in the presence of S1P. This shows a direct association of hepatocytes with hepatic stellate cells via S1P. Investigation of the underlying signaling pathways showed no change in SMADs but a decrease in p-AKT was seen consistently. Additionally, AKT inhibitors also showed a decrease in collagen message and expression after TGFβ induced activation of hepatic stellate cells. These results show that estrogen protects from NAFLD via regulating S1P which has an antifibrotic role in liver. This is the first evidence that S1P has antifibrotic roles contrary to the current literature. Our results show that the antifibrotic role of S1P is possibly due to AKT pathway irrespective of TGFβ/SMAD signaling. Therefore, targeting S1P receptors can potentially be a novel therapy for NAFLD.
I see quite a few women in the audience, well I have some good news for you. It’s great to be a woman, you have a lower risk of developing autism, addiction, Schizophrenia, and now adding to this list liver damage. Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common liver disorder with an estimated economic impact of $292 billion in United States alone. Fibrosis is the first stage of liver damage and hence can be targeted for therapeutics. Interestingly pre-menopausal women are protected from fibrosis but the exact cause for this is not known. Our lab specializes in studying lipids which are the compounds used for energy storage, signaling, and they also form structures of our cellular membranes. A lipid in which we are particularly interested is named Sphingosine 1 phosphate or S1P, it has been known to be a critical regulator of many important physiological functions including cancer, diabetes, and fibrosis. It also has a reputation of being the bad guy or a villain as it promotes fibrosis in multiple organs, therefore our lab created a mouse model in which liver cells were unable to produce this lipid. The reasoning behind this was simple that by removing this villain we can get rid of fibrosis and that is exactly what we saw in male mice which were protected from high fat diet induced fibrosis, but to our surprise female mice which are usually protected had severe liver damage. It is something that has not been seen before. Upon further investigation we observed that a female sex hormone known as estrogen promotes S1P which in turn protects livers from damage. This study reveals two important things 1) The notorious bad guy named S1P has in fact been the knight and shining armor for women all along. 2) One organ’s villain is another organ’s hero, S1P which has been shown to cause fibrosis in other organs has an opposite role in liver. Therefore, by keeping these two points in mind we can now use this knowledge to develop therapies specifically targeted towards liver damage and we can finally balance out this tipping scale.
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