Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipoproteins have a vital role in the development of metabolic and cardiovascular diseases ranging from protective to deleterious effects on target tissues. VLDL has been shown to induce lipotoxic lipid accumulation and exert a variety of negative effects on cardiomyocytes. Lipotoxicity and endoplasmic reticulum (ER) stress are proposed to be the mediators of damaging effects of metabolic diseases on cardiovascular system. We treated cardiomyocytes with lipoproteins to evaluate the adaptability of these cells to metabolic stress induced by starvation and excess of lipoproteins, and to evaluate the effect of lipoproteins and lipid accumulation on ER stress. VLDL reversed metabolic stress induced by starvation, while HDL did not. VLDL induced dose-dependent lipid accumulation in cardiomyocytes, which however did not result in reduced cell viability or induction of ER stress. Moreover, VLDL or HDL pre-treatment reduced ER stress in cardiomyocytes induced by tunicamycin and palmitic acid as measured by the expression of ER stress markers, even in conditions of increased lipid accumulation. VLDL and HDL induced activation of pro-survival ERK1/2 in cardiomyocytes; however, this activation was not involved in the protection against ER stress. Additionally, we observed that LDLR and VLDLR are regulated differently by lipoproteins and cellular stress, as lipoproteins induced VLDLR protein independently of the level of lipid accumulation. We conclude that VLDL is not a priori detrimental for cardiomyocytes and can even have beneficial effects, enabling cell survival under starvation and attenuating ER stress.
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PMID:VLDL and HDL attenuate endoplasmic reticulum and metabolic stress in HL-1 cardiomyocytes. 3233 Jun 63

The de novo synthesis of fatty acids has emerged as a therapeutic target for various diseases, including cancer. Because cancer cells are intrinsically buffered to combat metabolic stress, it is important to understand how cells may adapt to the loss of de novo fatty acid biosynthesis. Here, we use pooled genome-wide CRISPR screens to systematically map genetic interactions (GIs) in human HAP1 cells carrying a loss-of-function mutation in fatty acid synthase (FASN), whose product catalyses the formation of long-chain fatty acids. FASN-mutant cells show a strong dependence on lipid uptake that is reflected in negative GIs with genes involved in the LDL receptor pathway, vesicle trafficking and protein glycosylation. Further support for these functional relationships is derived from additional GI screens in query cell lines deficient in other genes involved in lipid metabolism, including LDLR, SREBF1, SREBF2 and ACACA. Our GI profiles also identify a potential role for the previously uncharacterized gene C12orf49 (which we call LUR1) in regulation of exogenous lipid uptake through modulation of SREBF2 signalling in response to lipid starvation. Overall, our data highlight the genetic determinants underlying the cellular adaptation associated with loss of de novo fatty acid synthesis and demonstrate the power of systematic GI mapping for uncovering metabolic buffering mechanisms in human cells.
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PMID:Systematic mapping of genetic interactions for de novo fatty acid synthesis identifies C12orf49 as a regulator of lipid metabolism. 3269 31