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      Lipid droplet biogenesis and functions in health and disease

      review-article
      , ,
      Nature Reviews. Endocrinology
      Nature Publishing Group UK
      Obesity, Cell biology

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          Abstract

          Ubiquitous yet unique, lipid droplets are intracellular organelles that are increasingly being recognized for their versatility beyond energy storage. Advances uncovering the intricacies of their biogenesis and the diversity of their physiological and pathological roles have yielded new insights into lipid droplet biology. Despite these insights, the mechanisms governing the biogenesis and functions of lipid droplets remain incompletely understood. Moreover, the causal relationship between the biogenesis and function of lipid droplets and human diseases is poorly resolved. Here, we provide an update on the current understanding of the biogenesis and functions of lipid droplets in health and disease, highlighting a key role for lipid droplet biogenesis in alleviating cellular stresses. We also discuss therapeutic strategies of targeting lipid droplet biogenesis, growth or degradation that could be applied in the future to common diseases, such as cancer, hepatic steatosis and viral infection.

          Abstract

          This Review outlines our current understanding of the biogenesis and functions of lipid droplets in health and disease, highlighting a key role for lipid droplet biogenesis in alleviating cellular stress.

          Key points

          • The primary roles of lipid droplet biogenesis are to alleviate cellular stress and maintain energy homeostasis.

          • Excess accumulation of lipid droplets and mutations in genes associated with lipid droplets are implicated in a plethora of pathologies.

          • Although they are beneficial to cell physiology under most conditions, lipid droplets might also exacerbate cytotoxicity and disease progression in certain disease settings.

          • Therapies targeting lipid droplet biogenesis, growth and degradation might be promising avenues for treating cancer, viral infection and hepatic steatosis.

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          Most cited references328

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          Ferroptosis: an iron-dependent form of nonapoptotic cell death.

          Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.
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            MAFLD: A consensus-driven proposed nomenclature for metabolic associated fatty liver disease

            Fatty liver associated with metabolic dysfunction is common, affects a quarter of the population, and has no approved drug therapy. Although pharmacotherapies are in development, response rates appear modest. The heterogeneous pathogenesis of metabolic fatty liver diseases and inaccuracies in terminology and definitions necessitate a reappraisal of nomenclature to inform clinical trial design and drug development. A group of experts sought to integrate current understanding of patient heterogeneity captured under the acronym nonalcoholic fatty liver disease (NAFLD) and provide suggestions on terminology that more accurately reflects pathogenesis and can help in patient stratification for management. Experts reached consensus that NAFLD does not reflect current knowledge, and metabolic (dysfunction) associated fatty liver disease "MAFLD" was suggested as a more appropriate overarching term. This opens the door for efforts from the research community to update the nomenclature and subphenotype the disease to accelerate the translational path to new treatments.
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              Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease

              Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem of unknown etiology that varies in prevalence among ethnic groups. To identify genetic variants contributing to differences in hepatic fat content, we performed a genome-wide association scan of nonsynonymous sequence variations (n=9,229) in a multiethnic population. An allele in PNPLA3 (rs738409; I148M) was strongly associated with increased hepatic fat levels (P=5.9×10−10) and with hepatic inflammation (P=3.7×10−4). The allele was most common in Hispanics, the group most susceptible to NAFLD; hepatic fat content was > 2-fold higher in PNPLA3-148M homozygotes than in noncarriers. Resequencing revealed another allele associated with lower hepatic fat content in African-Americans, the group at lowest risk of NAFLD. Thus, variation in PNPLA3 contributes to ethnic and inter-individual differences in hepatic fat content and susceptibility to NAFLD.
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                Author and article information

                Contributors
                h.rob.yang@unsw.edu.au
                Journal
                Nat Rev Endocrinol
                Nat Rev Endocrinol
                Nature Reviews. Endocrinology
                Nature Publishing Group UK (London )
                1759-5029
                1759-5037
                23 May 2023
                : 1-17
                Affiliations
                GRID grid.1005.4, ISNI 0000 0004 4902 0432, School of Biotechnology and Biomolecular Sciences, , The University of New South Wales, ; Sydney, NSW Australia
                Author information
                http://orcid.org/0000-0002-8482-6031
                Article
                845
                10.1038/s41574-023-00845-0
                10204695
                37221402
                01c2c1dc-2fb0-477a-ade0-a3da55f7d68e
                © Springer Nature Limited 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 25 April 2023
                Categories
                Review Article

                obesity,cell biology
                obesity, cell biology

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