Significance: Nonalcoholic fatty liver disease (NAFLD) is a common chronic hepatic disease affecting up to 25% of subjects in the developed world, and represents a progressive illness eventually leading to liver fibrosis and cirrhosis. This study reports an extensive set of human liver lipid droplet (LD)-associated proteins and an array of proteins differentially expressed in human NAFLD. We also uncover 17β-hydroxysteroid dehydrogenase-13, a newly identified LD-associated protein, as a pathogenic molecule in the development of NAFLD. The present study provides a potential link between LD proteins and the pathogenesis of hepatic steatosis.

The role of estrogen receptor (ER) α as a target in treatment of breast cancer is clear, but those of ERβ1 and ERβ2 in the breast remain unclear. We have examined expression of all three receptors in surgically excised breast samples from two archives: (i): 187 invasive ductal breast cancer from a Japanese study; and (ii) 20 lobular and 24 ductal cancers from the Imperial College. Samples contained normal areas, areas of hyperplasia, and in situ and invasive cancer. In the normal areas, ERα was expressed in not more than 10% of epithelium, whereas approximately 80% of epithelial cells expressed ERβ. We found that whereas ductal cancer is a highly proliferative, ERα-positive, ERβ-negative disease, lobular cancer expresses both ERα and ERβ but with very few Ki67-positive cells. ERβ2 was expressed in 32% of the ductal cancers, of which 83% were postmenopausal. In all ERβ2-positive cancers the interductal space was filled with dense collagen, and cell nuclei expressed hypoxia-inducible factor 1α. ERβ2 expression was not confined to malignant cells but was strong in stromal, immune, and endothelial cells. In most of the high-grade invasive ductal cancers neither ERα nor ERβ was expressed, but in the high-grade lobular cancer ERβ was lost and ERα and Ki67 expression were abundant. The data show a clear difference in ER expression between lobular and ductal breast cancer and suggest (i) that tamoxifen may be more effective in late than in early lobular cancer and (ii) a potential role for ERβ agonists in preventing in situ ductal cancers from becoming invasive. Significance Whether breast cancer will respond to the antiestrogen tamoxifen is determined by whether cellular proliferation is estrogen receptor (ER) α-mediated. As opposed to early ductal cancer, which is an ERα-rich, proliferating disease, in early lobular cancer both ERα and ERβ are abundantly expressed and proliferation is rare. In advanced lobular cancer, ERβ is lost, ERα is retained, and proliferation is high. Thus, tamoxifen may be an effective pharmaceutical in late but not early lobular cancer.

A therapeutic goal in the treatment of certain CNS diseases, including multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson disease, is to down-regulate inflammatory pathways. Inflammatory molecules produced by microglia are responsible for removal of damaged neurons, but can cause collateral damage to normal neurons located close to defective neurons. Although estrogen can inactivate microglia and inhibit the recruitment of T cells and macrophages into the CNS, there is controversy regarding which of the two estrogen receptors (ERs), ERα or ERβ, mediates the beneficial effects in microglia. In this study, we found that ERβ, but not ERα, is expressed in microglia. Using the experimental autoimmune encephalomyelitis (EAE) model in SJL/J mice, we evaluated the benefit of an ERβ agonist as a modulator of neuroinflammation. Treatment of EAE mice with LY3201, a selective ERβ agonist provided by Eli Lilly, resulted in marked reduction of activated microglia in the spinal cord. LY3201 down-regulated the nuclear transcription factor NF - κB, as well as the NF-κB–induced gene inducible nitric oxide synthase in microglia and CD3 ⁺ T cells. In addition, LY3201 inhibited T-cell reactivity through regulation of indoleamine-2,3-dioxygenase. In the EAE model, treatment with LY3201 decreased mortality in the first 2 wk after disease onset, and also reduced the severity of symptoms in mice surviving for 4 wk. Our data show that ERβ-selective agonists, by modulating the immune system in both microglia and T cells, offer promise as a useful class of drugs for treating degenerative diseases of the CNS.

Nuclear receptors (NRs) are transcription factors actively involved in many aspects of human physiology and pathology, serving as sensors of stimuli, master regulators of downstream molecular events and hubs governing complex gene regulatory networks. The importance of various members of the NR superfamily in cancer has led to substantial efforts to target them therapeutically. Notably, drugs that block the action of estrogen receptor alpha (ERα) in patients with ERα+ breast cancer or the androgen receptor (AR) in prostate cancer patients have provided remarkable improvements in survival. However, there is continuing need for novel drugs that target ERα or AR owing to resistance to established drugs, and there are also promising opportunities for targeting other nuclear receptors in cancer. In this article, we overview NR-based drug discovery in cancer and related resistance mechanisms, focusing on novel strategies for targeting well-established NR targets, including ERα, AR, the glucocorticoid receptor and the progesterone receptor, as well as opportunities to target other NRs that are attracting interest in immuno-oncology, such as liver X receptors (LXRs), RAR-related orphan receptors (RORs) and farnesoid X receptors (FXRs).