Neonatal intake of Omega-3 fatty acids enhances lipid oxidation in adipocyte precursors

Varshney, Rohan; Das, Snehasis; Trahan, G. Devon; Farriester, Jacob W.; Mullen, Gregory P.; Kyere-Davies, Gertrude; Presby, David M.; Houck, Julie A.; Webb, Patricia G.; Dzieciątkowska, Monika; Jones, Kenneth L.; Rodeheffer, Matthew S.; Friedman, Jacob E.; MacLean, Paul S.; Rudolph, Michael C.

doi:10.1016/j.isci.2022.105750

“…Total RNA from cultured cells was extracted and processed identically to that of mouse liver described above. Total protein from cultured cells was extracted and processed identically to that of mouse liver described above, with the exception that western blots were ran on the Jess SimpleWestern System (R&D Systems) as described previously 78 due to low protein abundance. Both primary antibodies utilized have been commercially validated and include SCD1 (Abcam; 1:25) and GAPDH (Abcam; 1:50).…”

Section: Methodsmentioning

confidence: 99%

Metabolic benefits of 17α-estradiol in liver are partially mediated by ERβ in male mice

Mondal

¹

,

Mann

²

,

Linden

³

et al. 2023

Preprint

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Metabolic dysfunction underlies several chronic diseases. Dietary interventions can reverse metabolic declines and slow aging but remaining compliant is difficult. 17α-estradiol (17α-E2) treatment improves metabolic parameters and slows aging in male mice without inducing significant feminization. We recently reported that estrogen receptor α is required for the majority of 17α-E2-mediated benefits in male mice, but that 17α-E2 also attenuates fibrogenesis in liver, which is regulated by estrogen receptor β (ERβ)-expressing hepatic stellate cells (HSC). The current studies sought to determine if 17α-E2-mediated benefits on systemic and hepatic metabolism are ERβ-dependent. We found that 17α-E2 treatment reversed obesity and related systemic metabolic sequela in both male and female mice, but this was partially blocked in female, but not male, ERβKO mice. ERβ ablation in male mice attenuated 17α-E2-mediated benefits on hepatic stearoyl-coenyzme A desaturase 1 (SCD1) and transforming growth factor β1 (TGF-β1) production, which play critical roles in HSC activation and liver fibrosis. We also found that 17α-E2 treatment suppresses SCD1 production in cultured hepatocytes and hepatic stellate cells, indicating that 17α-E2 directly signals in both cell-types to suppress drivers of steatosis and fibrosis. We conclude that ERβ partially controls 17α-E2-mediated benefits on systemic metabolic regulation in female, but not male, mice, and that 17α-E2 likely signals through ERβ in HSCs to attenuate pro-fibrotic mechanisms.

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“…Total RNA from cultured cells was extracted and processed identically to that of mouse liver described above. Total protein from cultured cells was extracted and processed identically to that of mouse liver described above, with the exception that western blots were ran on the Jess SimpleWestern System (R&D Systems) as described previously 79 due to low protein abundance. Both primary antibodies utilized have been commercially validated and include SCD1 (Abcam; 1:25) and GAPDH (Abcam; 1:50).…”

Section: Methodsmentioning

confidence: 99%

Metabolic benefits of 17α-estradiol in liver are partially mediated by ERβ in male mice

Mondal

¹

,

Mann

²

,

Linden

³

et al. 2023

Sci Rep

Self Cite

8

0

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Metabolic dysfunction underlies several chronic diseases. Dietary interventions can reverse metabolic declines and slow aging but remaining compliant is difficult. 17α-estradiol (17α-E2) treatment improves metabolic parameters and slows aging in male mice without inducing significant feminization. We recently reported that estrogen receptor α is required for the majority of 17α-E2-mediated benefits in male mice, but that 17α-E2 also attenuates fibrogenesis in liver, which is regulated by estrogen receptor β (ERβ)-expressing hepatic stellate cells (HSC). The current studies sought to determine if 17α-E2-mediated benefits on systemic and hepatic metabolism are ERβ-dependent. We found that 17α-E2 treatment reversed obesity and related systemic metabolic sequela in both male and female mice, but this was partially blocked in female, but not male, ERβKO mice. ERβ ablation in male mice attenuated 17α-E2-mediated benefits on hepatic stearoyl-coenyzme A desaturase 1 (SCD1) and transforming growth factor β1 (TGF-β1) production, which play critical roles in HSC activation and liver fibrosis. We also found that 17α-E2 treatment suppresses SCD1 production in cultured hepatocytes and hepatic stellate cells, indicating that 17α-E2 directly signals in both cell-types to suppress drivers of steatosis and fibrosis. We conclude that ERβ partially controls 17α-E2-mediated benefits on systemic metabolic regulation in female, but not male, mice, and that 17α-E2 likely signals through ERβ in HSCs to attenuate pro-fibrotic mechanisms.

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“…Data were acquired in full scan negative chemical ionization mode to identify fatty acids of acyl chain length from 8 to 22 carbons. Peak areas of the analyte or of the standard were measured, and the ratio of the area from the analyte-derived ion to that from the internal standard was calculated [23]. 13 C2-acetate tracer incorporation into palmitic acid was analyzed in two carbon increments from M+2 (257 m/z) to M+16 (271 m/z) relative to the quantitative 2 D31palmitate internal standard [24][25][26].…”

Section: Targeted Lipid Mass Spectrometrymentioning

confidence: 99%

Targeting aberrant fatty acid synthesis and storage in endocrine resistant breast cancer cells

Ward,

Riley,

Finlay-Schultz

et al. 2024

Preprint

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BackgroundLipid metabolic reprogramming is an emerging characteristic of endocrine therapy (ET) resistance in estrogen receptor-positive (ER+) breast cancer. We explored changes in lipid metabolism in ER+ breast cancer cell lines following acquired resistance to common endocrine treatments and tested efficacy of an inhibitor in current clinical trials.MethodsWe derived ER+ breast cancer cell lines resistant to Tamoxifen (TamR), Fulvestrant (FulvR), and long-term estrogen withdrawal (EWD). Parental and ET resistant cells were subjected to global gene expression and unbiased lipidomic profiling. Lipid storage changes were assessed via neutral lipid staining with Oil Red O (ORO). The impact of the fatty acid synthase (FASN) inhibitor TVB-2640 on the growth and lipid storage of these cell lines was evaluated. Additionally,13C2-acetate tracing was used to examine FASN activity in parental and ET resistant cells in the absence or presence of TVB-2640.ResultsCompared to parental cells, lipid metabolism and processing pathways were notably enriched in ET resistant cells, which exhibited distinct lipidomes characterized by increased triglyceride and polyunsaturated FA (PUFA) species. ET-resistant cells displayed enhanced cytoplasmic lipid droplets. Increased FASN protein levels were observed in ET-resistant cells, and TVB-2640 effectively inhibited FASN activity. FASN inhibition reduced cell growth in some but not all cell lines and ET resistance types and did not correlate to lipid storage reduction.13C2-acetate tracing confirmed reduced palmitate synthesis and enhanced PUFA synthesis in ET-resistant cells, especially when combined with FulvR.ConclusionET resistant breast cancer cells exhibit a shift towards enhanced triglyceride storage and complex lipids enriched with PUFA acyl chains. While targeting FASN alongside ET may not fully overcome ET resistance in our models, focusing on the unique lipid metabolic dependencies, such as PUFA pathways, may present a promising alternative strategy for treating ET resistant breast cancer.

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Neonatal intake of Omega-3 fatty acids enhances lipid oxidation in adipocyte precursors

Cited by 7 publications

References 85 publications

Metabolic benefits of 17α-estradiol in liver are partially mediated by ERβ in male mice

Metabolic benefits of 17α-estradiol in liver are partially mediated by ERβ in male mice

Metabolic benefits of 17α-estradiol in liver are partially mediated by ERβ in male mice

Targeting aberrant fatty acid synthesis and storage in endocrine resistant breast cancer cells

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