Inhibition of protein arginine methyltransferase 5 enhances hepatic mitochondrial biogenesis

Protein arginine methyltransferase 5 (PRMT5) regulates gene expression either transcriptionallyly by symmetric dimethylation of arginine residues on histones H4R3, H3R8 and H2AR3, or at the post-translational level by methylation of non-histone target proteins. While emerging evidence suggests that PRMT5 functions as an oncogene, its role in metabolic diseases is not well defined. We investigated the role of PRMT5 in promoting high fat-induced hepatic steatosis. High fat diet up-regulated PRMT5 levels in the liver, but not in other metabolically relevant tissues such as skeletal muscle or white and brown adipose tissue. This was associated with repression of master transcription regulators involved in mitochondrial biogenesis. In contrast, lentiviral shRNA-mediated reduction of PRMT5 significantly decreased PI3K/AKT signaling in mouse AML12 liver cells. PRMT5 knockdown or knockout decreased basal AKT phosphorylation, but boosted the expression of PPARalpha and PGC-1alpha with a concomitant increase of mitochondrial biogenesis. Moreover, by overexpressing an exogenous wild-type or enzyme-dead mutant PRMT5, or by inhibiting PRMT5 enzymatic activity with a small molecule inhibitor, we demonstrated that the enzymatic activity of PRMT5 is required for regulation of PPARalpha and PGC-1alpha expression and mitochondrial biogenesis. Our results suggest that targeting PRMT5 may have therapeutic potential for treatment of fatty liver. Biology, Inc

High-calorie diet exacerbates prostate neoplasia in mice with haploinsufficiency of Pten tumor suppressor gene

Objective: Association between prostate cancer and obesity remains controversial. Allelic deletions of PTEN, a tumor suppressor gene, are common in prostate cancer in men. Monoallelic Pten deletion in mice causes low prostatic intraepithelial neoplasia (mPIN). This study tested the effect of a hypercaloric diet on prostate cancer in Pten+/− mice. Methods: 1-month old mice were fed a high-calorie diet deriving 45% calories from fat for 3 and 6 months before prostate was analyzed histologically and biochemically for mPIN progression. Because Pten+/− mice are protected against diet-induced insulin resistance, we tested the role of insulin on cell growth in RWPE-1 normal human prostatic epithelial cells with siRNA knockdown of PTEN. Results: In addition to activating PI3 kinase/Akt and Ras/MAPkinase pathways, high-calorie diet causes neoplastic progression, angiogenesis, inflammation and epithelial–mesenchymal transition. It also elevates the expression of fatty acid synthase (FAS), a lipogenic gene commonly elevated in progressive cancer. SiRNA-mediated downregulation of PTEN demonstrates increased cell growth and motility, and soft agar clonicity in addition to elevation in FAS in response to insulin in RWPE-1 normal human prostatic cells. Downregulating FAS in addition to PTEN, blunted the proliferative effect of insulin (and IL-6) in RWPE-1 cells. Conclusion: High-calorie diet promotes prostate cancer progression in the genetically susceptible Pten haploinsufficient mouse while preserving insulin sensitivity. This appears to be partly due to increased inflammatory response to high-caloric intake in addition to increased ability of insulin to promote lipogenesis