Triglyceride-derived fatty acids reduce autophagy in a model of retinal angiomatous proliferation

被引：16

作者：

Heckel, Emilie ^{[1
]}

Cagnone, Gael ^{[1
]}

Agnihotri, Tapan ^{[2
]}

Cakir, Bertan ^{[3
]}

Das, Ashim ^{[1
]}

Kim, Jin Sung ^{[2
]}

Kim, Nicholas ^{[2
]}

Lavoie, Genevieve ^{[4
]}

Situ, Anu ^{[5
]}

Pundir, Sheetal ^{[2
]}

Sun, Ye ^{[3
]}

Wunnemann, Florian ^{[5
]}

Pierce, Kerry A. ^{[6
]}

Dennis, Courtney ^{[6
]}

Mitchell, Grant A. ^{[5
]}

Chemtob, Sylvain ^{[1
,2
,5
,7
]}

Rezende, Flavio A. ^{[7
]}

Andelfinger, Gregor ^{[5
]}

Clish, Clary B. ^{[6
]}

Roux, Philippe P. ^{[4
]}

Sapieha, Przemyslaw ^{[7
]}

Smith, Lois Eh ^{[3
]}

Joyal, Jean-Sebastien ^{[1
,2
,5
,7
]}

机构：

[1] Univ Montreal, Dept Pharmacol, Montreal, PQ, Canada

[2] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ, Canada

[3] Harvard Med Sch, Dept Ophthalmol, Boston Childrens Hosp, Boston, MA 02115 USA

[4] Inst Res Immunol & Canc IRIC, Dept Pathol & Cell Biol, Montreal, PQ, Canada

[5] Univ Montreal, Dept Pediat, Montreal, PQ, Canada

[6] Broad Inst MIT & Harvard Univ, Metabol Platform, Cambridge, MA USA

[7] Univ Montreal, Dept Ophthalmol, Montreal, PQ, Canada

来源：

JCI INSIGHT | 2022年 / 7卷 / 06期

基金：

加拿大自然科学与工程研究理事会; 加拿大创新基金会; 加拿大健康研究院;

关键词：

MOUSE MODEL; KINASE-II; CALCINEURIN; METABOLISM; EXPRESSION; GLUCOSE; LIPIDS; CELLS; NEOVASCULARIZATION; PHOSPHORYLATION;

D O I：

10.1172/jci.insight.154174

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Dyslipidemia and autophagy have been implicated in the pathogenesis of blinding neovascular age-related macular degeneration (NV-AMD). VLDL receptor (VLDLR), expressed in photoreceptors with a high metabolic rate, facilitates the uptake of triglyceride-derived fatty acids. Since fatty acid uptake is reduced in Vldlr(-/-) tissues, more remain in circulation, and the retina is fuel deficient, driving the formation in mice of neovascular lesions reminiscent of retinal angiomatous proliferation (RAP), a subtype of NV-AMD. Nutrient scarcity and energy failure are classically mitigated by increasing autophagy. We found that excess circulating lipids restrained retinal autophagy, which contributed to pathological angiogenesis in the Vldlr(-/-) RAP model. Triglyceride-derived fatty acid sensed by free fatty acid receptor 1 (FFAR1) restricted autophagy and oxidative metabolism in photoreceptors. FFAR1 suppressed transcription factor EB (TFEB), a master regulator of autophagy and lipid metabolism. Reduced TFEB, in turn, decreased sirtuin-3 expression and mitochondrial respiration. Meta bolomic signatures of mouse RAP-like retinas were consistent with a role in promoting angiogenesis. This signature was also found in human NV-AMD vitreous. Restoring photoreceptor autophagy in Vldlr(-/-) retinas, either pharmacologically or by deleting Ffar1, enhanced metabolic efficiency and suppressed pathological angiogenesis. Dysregulated autophagy by circulating lipids might therefore contribute to the energy failure of photoreceptors driving neovascular eye diseases, and FFAR1 may be a target for intervention.

引用

页数：16

共 67 条

[11] Antioxidant or neurotrophic factor treatment preserves function in a mouse model of neovascularization-associated oxidative stress [J].