Dropping in on lipid droplets: insights into cellular stress and cancer

Shyu, Peter; Wong, Xing Fah Alex; Crasta, Karen; Thibault, Guillaume

doi:10.1042/bsr20180764

Cited by 65 publications

(52 citation statements)

References 224 publications

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“…Acetylated proteins are also involved in the degradation of unfolded protein aggregates (ERAD) as well as in autophagy [43]. Moreover, lipid droplets have been proposed as a temporary depot for proteins destined for degradation by ERAD [45]. Therefore, considering the role of ACLY in both lipogenesis and protein acetylation, the increase of ACLY expression observed in ER-stressed cells could indicate an ACLY function in maintaining the proteostatic balance in the cell.…”

Section: Discussionmentioning

confidence: 99%

In Steatotic Cells, ATP-Citrate Lyase mRNA Is Efficiently Translated through a Cap-Independent Mechanism, Contributing to the Stimulation of De Novo Lipogenesis

Siculella

Giannotti

Testini

et al. 2020

IJMS

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Non-alcoholic fatty liver disease (NAFLD) is a chronic disease in which excessive amount of lipids is accumulated as droplets in hepatocytes. Recently, cumulative evidences suggested that a sustained de novo lipogenesis can play an important role in NAFLD. Dysregulated expression of lipogenic genes, including ATP-citrate lyase (ACLY), has been found in liver diseases associated with lipid accumulation. ACLY is a ubiquitous cytosolic enzyme positioned at the intersection of nutrients catabolism and cholesterol and fatty acid biosyntheses. In the present study, the molecular mechanism of ACLY expression in a cell model of steatosis has been reported. We identified an internal ribosome entry site (IRES) in the 5 untranslated region of the ACLY mRNA, that can support an efficient mRNA translation through a Cap-independent mechanism. In steatotic HepG2 cells, ACLY expression was up-regulated through IRES-mediated translation. Since it has been demonstrated that lipid accumulation in cells induces endoplasmic reticulum (ER) stress, the involvement of this cellular pathway in the translational regulation of ACLY has been also evaluated. Our results showed that ACLY expression was increased in ER-stressed cells, through IRES-mediated translation of ACLY mRNA. A potential role of the Cap-independent translation of ACLY in NAFLD has been discussed. Int. J. Mol. Sci. 2020, 21, 1206 48 h of treatment ( Figure 1B). In agreement with previous results [9], treatment with FFAs caused an increment of SREBP-1 mRNA abundance ( Figure 1A). The content of precursor (pSREBP-1) and active nuclear (nSREBP-1) of SREBP-1 protein increased in FFAs-treated cells with respect to control ( Figure 1B). Int. J. Mol. Sci. 2020, 21, 1206 Then ACLY levels showed a constant increase, becoming about 3.5-fold greater than the control after 48 h of treatment ( Figure 1B). In agreement with previous results [9], treatment with FFAs caused an increment of SREBP-1 mRNA abundance ( Figure 1A). The content of precursor (pSREBP-1) and active nuclear (nSREBP-1) of SREBP-1 protein increased in FFAs-treated cells with respect to control ( Figure 1B).

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Section: Discussionmentioning

confidence: 99%

In Steatotic Cells, ATP-Citrate Lyase mRNA Is Efficiently Translated through a Cap-Independent Mechanism, Contributing to the Stimulation of De Novo Lipogenesis

Siculella

Giannotti

Testini

et al. 2020

IJMS

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“…Additionally, adipocyte-derived FFAs can also be incorporated into phospholipids and esterified with cholesterol to produce cholesteryl esters in cell membranes (73,74) to induce lipid-saturated membranes. This is further supported by the increased amount and size of lipid droplets found in breast cancer tumors, specifically more aggressive phenotypes (6,73).…”

Section: Diet-induced Obesity Distinctly Alters Lipid Metabolism In Tmentioning

confidence: 99%

Decreased Efficacy of Doxorubicin Corresponds With Modifications in Lipid Metabolism Markers and Fatty Acid Profiles in Breast Tumors From Obese vs. Lean Mice

et al. 2020

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Breast cancer cells modulate lipid and fatty acid metabolism to sustain proliferation. The role of adipocytes in cancer treatment efficacy remains, however, to be fully elucidated. We investigated whether diet-induced obesity (DIO) affects the efficacy of doxorubicin treatment in a breast tumor-bearing mouse model. Female C57BL6 mice were fed a high fat or low fat diet for the full duration of the study (12 weeks). After 8 weeks, mice were inoculated with E0771 triple-negative breast cancer cells in the fourth mammary gland to develop breast tumor allographs. Tumor-bearing mice received either vehicle (Hank's balanced salt solution) or doxorubicin (chemotherapy). Plasma inflammatory markers, tumor, and mammary adipose tissue fatty acid composition, as well as protein expression of lipid metabolism markers were determined. The high fat diet (HFD) attenuated the treatment efficacy of doxorubicin. Both leptin and resistin concentrations were significantly increased in the HFD group treated with doxorubicin. Suppressed lipogenesis (decreased stearoyl CoA-desaturase-1) and lipolysis (decreased hormone-sensitive lipase) were observed in mammary adipose tissue of the DIO animals, whereas increased expression was observed in the tumor tissue of doxorubicin treated HFD mice. Obesogenic conditions induced altered tissue fatty acid (FA) compositions, which reduced doxorubicin's treatment efficacy. In mammary adipose tissue breast cancer cells suppressed the storage of FAs, thereby increasing the availability of free FAs and favored inflammation under obesogenic conditions.

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“…Lipid droplets (LDs) are intracellular oil-in-water emulsion droplets, present in almost all organisms and playing diverse biological functions (Olzmann and Carvalho, 2019; Thiam and Beller, 2017; Welte, 2015). They primarily function to maintain cellular energy balance (Walther and Farese, 2012) but are also implicated in several other mechanisms such as protein quality control or lipid stress response (Bersuker and Olzmann, 2017; Shyu et al, 2018). The oil core of LDs is made of neutral lipids whose composition varies between cell types and metabolic conditions (Walther and Farese, 2012).…”

Section: Introductionmentioning

confidence: 99%

Neutral lipids regulate amphipathic helix affinity for model lipid droplets

Chorlay

Thiam

2020

Journal of Cell Biology

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Cellular lipid droplets (LDs) have a neutral lipid core shielded from the aqueous environment by a phospholipid monolayer containing proteins. These proteins define the biological functions of LDs, and most of them bear amphipathic helices (AH), which can selectively target to LDs, or to LD subsets. How such binding preference happens remains poorly understood. Here, we found that artificial LDs made of different neutral lipids but presenting equal phospholipid packing densities differentially recruit AHs. Varying the phospholipid density shifts the binding levels, but the differential recruitment is unchanged. We found that the binding level of AHs is defined by their interaction preference with neutral lipids and ability to decrease surface tension. The phospholipid packing level regulates mainly the amount of neutral lipid accessible. Therefore, it is the hydrophobic nature of the phospholipid packing voids that controls the binding level of AHs. Our data bring us a major step closer to understanding the binding selectivity of AHs to lipid membranes.

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Dropping in on lipid droplets: insights into cellular stress and cancer

Cited by 65 publications

References 224 publications

In Steatotic Cells, ATP-Citrate Lyase mRNA Is Efficiently Translated through a Cap-Independent Mechanism, Contributing to the Stimulation of De Novo Lipogenesis

In Steatotic Cells, ATP-Citrate Lyase mRNA Is Efficiently Translated through a Cap-Independent Mechanism, Contributing to the Stimulation of De Novo Lipogenesis

Decreased Efficacy of Doxorubicin Corresponds With Modifications in Lipid Metabolism Markers and Fatty Acid Profiles in Breast Tumors From Obese vs. Lean Mice

Neutral lipids regulate amphipathic helix affinity for model lipid droplets

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