Supplementary key words mevalonate • lanosterol • sterol intermediates • 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation • sterol regulatory element-binding protein-2 cleavage • clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) • sterol regulatory element-binding protein-2 Cholesterol is an essential lipid for mammals. It regulates membrane fluidity and functions, serves as the precursor for steroid hormones and bile acids, and covalently modifies the Hedgehog and Smoothened proteins (1-3). A high level of blood cholesterol is a major risk factor for cardiovascular disease, and cholesterol lowering is an effective way to treat the cardiovascular disease (4-7). Cholesterol is synthesized from acetyl-CoA through over 30 steps of reactions (Fig. 1). The cholesterol biosynthetic pathway is also known as the mevalonate pathway. Mevalonate is a key intermediate synthesized from HMG-CoA by HMG-CoA reductase (HMGCR), an ER-localized ratelimiting enzyme of the mevalonate pathway (8). Cholesterol biosynthesis is governed by two feedback regulatory mechanisms: the sterol-induced degradation of HMGCR (9) and inactivation of SREBP-2, the latter of which controls transcription of the genes involved in cholesterol biosynthesis and uptake (10). When the cellular sterol level is Abstract Sterol-regulated HMG-CoA reductase (HMGCR) degradation and SREBP-2 cleavage are two major feedback regulatory mechanisms governing cholesterol biosynthesis. Reportedly, lanosterol selectively stimulates HMGCR degradation, and cholesterol is a specific regulator of SREBP-2 cleavage. However, it is unclear whether other endogenously generated sterols regulate these events. Here, we investigated the sterol intermediates from the mevalonate pathway of cholesterol biosynthesis using a CRISPR/Cas9mediated genetic engineering approach. With a constructed HeLa cell line expressing the mevalonate transporter, we individually deleted genes encoding major enzymes in the mevalonate pathway, used lipidomics to measure sterol intermediates, and examined HMGCR and SREBP-2 statuses. We found that the C4-dimethylated sterol intermediates, including lanosterol, 24,25-dihydrolanosterol, follicular fluid meiosis activating sterol, testis meiosis activating sterol, and dihydro-testis meiosis activating sterol, were significantly upregulated upon mevalonate loading. These intermediates augmented both degradation of HMGCR and inhibition of SREBP-2 cleavage. The accumulated lanosterol induced rapid degradation of HMGCR, but did not inhibit SREBP-2 cleavage. The newly synthesized cholesterol from the mevalonate pathway is dispensable for inhibiting SREBP-2 cleavage. Together, these results suggest that lanosterol is a bona fide endogenous regulator that specifically promotes HMGCR degradation, and that other C4-dimethylated sterol intermediates may regulate both HMGCR degradation and SREBP-2 cleavage.
This study aimed to integrate and analyze the existing studies and to explore research trends and hotspots related to the effects of xenobiotics on glucose metabolism in male testes. All articles were retrieved from the PubMed database, from an inception date up to 10 June 2017. CiteSpace software (version 5.1.R8 SE) was used for the co-word cluster analysis. A total of 165 eligible publications were included in this study. In 1949–1959, only two articles were published. After 1960, the number of articles increased steadily. These articles were published in 97 journals, in particular, in the Indian Journal of Experimental Biology (11 articles, 6.7%). Most of the authors (87.0%) only published one article. Only a few established research teams, mostly from the USA, worked consistently in this field. The main xenobiotics that had been studied were medicine and common environmental pollutants, e.g., gossypol, cadmium, di-n-butyl phthalate, and alpha-chlorohydrin. The hotspot keywords were Sertoli cell, lactate dehydrogenase, 6-phosphate dehydrogenase, oxidative stress, and glucose metabolism. The focus of research had been changed overtime. This is the first bibliometric study between xenobiotics and glucose metabolism in the male testes. The findings suggest that environmental pollutants have become a huge concern, and related research should be strengthened.
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