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Genetics-driven discovery of novel regulators of lipid metabolism.

ABSTRACT: PURPOSE OF REVIEW:Residual cardiovascular disease risk and increasing metabolic syndrome risk underscores a need for novel therapeutics targeting lipid metabolism in humans. Unbiased human genetic screens have proven powerful in identifying novel genomic loci, and this review discusses recent developments in such discovery. RECENT FINDINGS:Recent human genome-wide association studies have been completed in incredibly large, detailed cohorts, allowing for the identification of more than 300 genomic loci that participate in the regulation of plasma lipid metabolism. However, the discovery of these loci has greatly outpaced the elucidation of the underlying functional mechanisms. The identification of novel roles for long noncoding RNAs, such as CHROME, LeXis, and MeXis, in lipid metabolism suggests that noncoding RNAs should be included in the functional translation of GWAS loci. SUMMARY:Unbiased genetic studies appear to have unearthed a great deal of novel biology with respect to lipid metabolism, yet translation of these findings into actionable mechanisms has been slow. Increased focus on the translation, rather than the discovery, of these loci, with new attention paid to lncRNAs, can help spur the development of novel therapeutics targeting lipid metabolism.

SUBMITTER: Ha EE

PROVIDER: S-EPMC6681899 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Genetics-driven discovery of novel regulators of lipid metabolism.

Ha Elizabeth E EE Van Camp Andrew G AG Bauer Robert C RC

Current opinion in lipidology 20190601 3

<h4>Purpose of review</h4>Residual cardiovascular disease risk and increasing metabolic syndrome risk underscores a need for novel therapeutics targeting lipid metabolism in humans. Unbiased human genetic screens have proven powerful in identifying novel genomic loci, and this review discusses recent developments in such discovery.<h4>Recent findings</h4>Recent human genome-wide association studies have been completed in incredibly large, detailed cohorts, allowing for the identification of more ...[more]

PMID: 30985365

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Project description:BACKGROUND:Invasive lobular breast carcinoma (ILC) is a histological subtype of breast cancer that is characterized by loss of E-cadherin and high expression of estrogen receptor alpha (ER?). In many cases, ILC is effectively treated with adjuvant aromatase inhibitors (AIs); however, acquired AI resistance remains a significant problem. METHODS:To identify underlying mechanisms of acquired anti-estrogen resistance in ILC, we recently developed six long-term estrogen-deprived (LTED) variant cell lines from the human ILC cell lines SUM44PE (SUM44; two lines) and MDA-MB-134VI (MM134; four lines). To better understand mechanisms of AI resistance in these models, we performed transcriptional profiling analysis by RNA-sequencing followed by candidate gene expression and functional studies. RESULTS:MM134 LTED cells expressed ER at a decreased level and lost growth response to estradiol, while SUM44 LTED cells retained partial ER activity. Our transcriptional profiling analysis identified shared activation of lipid metabolism across all six independent models. However, the underlying basis of this signature was distinct between models. Oxysterols were able to promote the proliferation of SUM44 LTED cells but not MM134 LTED cells. In contrast, MM134 LTED cells displayed a high expression of the sterol regulatory element-binding protein 1 (SREBP1), a regulator of fatty acid and cholesterol synthesis, and were hypersensitive to genetic or pharmacological inhibition of SREBPs. Several SREBP1 downstream targets involved in fatty acid synthesis, including FASN, were induced, and MM134 LTED cells were more sensitive to etomoxir, an inhibitor of the rate-limiting enzyme in beta-oxidation, than their respective parental control cells. Finally, in silico expression analysis in clinical specimens from a neo-adjuvant endocrine trial showed a significant association between the increase of SREBP1 expression and lack of clinical response, providing further support for a role of SREBP1 in the acquisition of endocrine resistance in breast cancer. CONCLUSIONS:Our characterization of a unique series of AI-resistant ILC models identifies the activation of key regulators of fatty acid and cholesterol metabolism, implicating lipid-metabolic processes driving estrogen-independent growth of ILC cells. Targeting these changes may prove a strategy for prevention and treatment of endocrine resistance for patients with ILC.

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Genetics-driven discovery of novel regulators of lipid metabolism.

Publications

Genetics-driven discovery of novel regulators of lipid metabolism.

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