Download PDF
Semin Liver Dis 2023; 43(04): 367-382
DOI: 10.1055/a-2186-3557
Review Article

Mechanisms of Lipid Droplet Accumulation in Steatotic Liver Diseases

Joseph L. Dempsey
1   Division of Gastroenterology, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington
,
George N. Ioannou
1   Division of Gastroenterology, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington
2   Division of Gastroenterology, Veterans Affairs Puget Sound Healthcare System Seattle, Washington
,
Rotonya M. Carr
1   Division of Gastroenterology, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington
› Author Affiliations
› Further Information
   Permissions and Reprints


Abstract

The steatotic diseases of metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and chronic hepatitis C (HCV) account for the majority of liver disease prevalence, morbidity, and mortality worldwide. While these diseases have distinct pathogenic and clinical features, dysregulated lipid droplet (LD) organelle biology represents a convergence of pathogenesis in all three. With increasing understanding of hepatocyte LD biology, we now understand the roles of LD proteins involved in these diseases but also how genetics modulate LD biology to either exacerbate or protect against the phenotypes associated with steatotic liver diseases. Here, we review the history of the LD organelle and its biogenesis and catabolism. We also review how this organelle is critical not only for the steatotic phenotype of liver diseases but also for their advanced phenotypes. Finally, we summarize the latest attempts and challenges of leveraging LD biology for therapeutic gain in steatotic diseases. In conclusion, the study of dysregulated LD biology may lead to novel therapeutics for the prevention of disease progression in the highly prevalent steatotic liver diseases of MASLD, ALD, and HCV.

Keywords

steatotic liver disease - lipid droplet - lipid droplet proteins - perilipins - MASLD - alcohol-associated liver disease - hepatitis C


Publication History

Accepted Manuscript online:
05 October 2023

Article published online:
06 November 2023

© 2023. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Chi X, Ogunsade OO, Zhou Z. et al. Lipid droplet is an ancient and inheritable organelle in bacteria. bioRxiv 2020; DOI: 10.1101/2020.05.18.103093.
    CrossrefPubMedGoogle Scholar
  • 2 Martin S, Parton RG. Lipid droplets: a unified view of a dynamic organelle. Nat Rev Mol Cell Biol 2006; 7 (05) 373-378
    CrossrefPubMedGoogle Scholar
  • 3 Baselli G, Valenti L. Beyond fat accumulation, NAFLD genetics converges on lipid droplet biology. J Lipid Res 2019; 60 (01) 7-8
    CrossrefPubMedGoogle Scholar
  • 4 Wilfling F, Wang H, Haas JT. et al. Triacylglycerol synthesis enzymes mediate lipid droplet growth by relocalizing from the ER to lipid droplets. Dev Cell 2013; 24 (04) 384-399
    CrossrefPubMedGoogle Scholar
  • 5 Stone SJ, Levin MC, Zhou P, Han J, Walther TC, Farese Jr RV. The endoplasmic reticulum enzyme DGAT2 is found in mitochondria-associated membranes and has a mitochondrial targeting signal that promotes its association with mitochondria. J Biol Chem 2009; 284 (08) 5352-5361
    CrossrefPubMedGoogle Scholar
  • 6 Xu Y, Du X, Turner N, Brown AJ, Yang H. Enhanced acyl-CoA:cholesterol acyltransferase activity increases cholesterol levels on the lipid droplet surface and impairs adipocyte function. J Biol Chem 2019; 294 (50) 19306-19321
    CrossrefPubMedGoogle Scholar
  • 7 Long T, Sun Y, Hassan A, Qi X, Li X. Structure of nevanimibe-bound tetrameric human ACAT1. Nature 2020; 581 (7808) 339-343
    CrossrefPubMedGoogle Scholar
  • 8 Santinho A, Salo VT, Chorlay A. et al. Membrane curvature catalyzes lipid droplet assembly. Curr Biol 2020; 30 (13) 2481.e6-2494.e6
    CrossrefPubMedGoogle Scholar
  • 9 Zoni V, Khaddaj R, Campomanes P, Thiam AR, Schneiter R, Vanni S. Pre-existing bilayer stresses modulate triglyceride accumulation in the ER versus lipid droplets. eLife 2021; 10: 10
    CrossrefPubMedGoogle Scholar
  • 10 Kim S, Li C, Farese Jr RV, Walther TC, Voth GA. Key factors governing initial stages of lipid droplet formation. J Phys Chem B 2022; 126 (02) 453-462
    CrossrefPubMedGoogle Scholar
  • 11 Choudhary V, Ojha N, Golden A, Prinz WA. A conserved family of proteins facilitates nascent lipid droplet budding from the ER. J Cell Biol 2015; 211 (02) 261-271
    CrossrefPubMedGoogle Scholar
  • 12 Arlt H, Sui X, Folger B. et al. Seipin forms a flexible cage at lipid droplet formation sites. Nat Struct Mol Biol 2022; 29 (03) 194-202
    CrossrefPubMedGoogle Scholar
  • 13 Fei W, Shui G, Gaeta B. et al. Fld1p, a functional homologue of human seipin, regulates the size of lipid droplets in yeast. J Cell Biol 2008; 180 (03) 473-482
    CrossrefPubMedGoogle Scholar
  • 14 Wang CW, Miao YH, Chang YS. Control of lipid droplet size in budding yeast requires the collaboration between Fld1 and Ldb16. J Cell Sci 2014; 127 (Pt 6): 1214-1228
    PubMedGoogle Scholar
  • 15 Lukmantara I, Chen F, Mak HY. et al. PI(3)P and DFCP1 regulate the biogenesis of lipid droplets. Mol Biol Cell 2022; 33 (14) ar131
    CrossrefPubMedGoogle Scholar
  • 16 Szymanski KM, Binns D, Bartz R. et al. The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology. Proc Natl Acad Sci U S A 2007; 104 (52) 20890-20895
    CrossrefPubMedGoogle Scholar
  • 17 Cartwright BR, Binns DD, Hilton CL, Han S, Gao Q, Goodman JM. Seipin performs dissectible functions in promoting lipid droplet biogenesis and regulating droplet morphology. Mol Biol Cell 2015; 26 (04) 726-739
    CrossrefPubMedGoogle Scholar
  • 18 Correnti J, Lin C, Brettschneider J. et al. Liver-specific ceramide reduction alleviates steatosis and insulin resistance in alcohol-fed mice. J Lipid Res 2020; 61 (07) 983-994
    CrossrefPubMedGoogle Scholar
  • 19 Williams B, Correnti J, Oranu A. et al. A novel role for ceramide synthase 6 in mouse and human alcoholic steatosis. FASEB J 2018; 32 (01) 130-142
    CrossrefPubMedGoogle Scholar
  • 20 BasuRay S, Wang Y, Smagris E, Cohen JC, Hobbs HH. Accumulation of PNPLA3 on lipid droplets is the basis of associated hepatic steatosis. Proc Natl Acad Sci U S A 2019; 116 (19) 9521-9526
    CrossrefPubMedGoogle Scholar
  • 21 Trépo E, Gustot T, Degré D. et al. Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease. J Hepatol 2011; 55 (04) 906-912
    CrossrefPubMedGoogle Scholar
  • 22 Stickel F, Buch S, Lau K. et al. Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians. Hepatology 2011; 53 (01) 86-95
    CrossrefPubMedGoogle Scholar
  • 23 Tian C, Stokowski RP, Kershenobich D, Ballinger DG, Hinds DA. Variant in PNPLA3 is associated with alcoholic liver disease. Nat Genet 2010; 42 (01) 21-23
    CrossrefPubMedGoogle Scholar
  • 24 Dongiovanni P, Donati B, Fares R. et al. PNPLA3 I148M polymorphism and progressive liver disease. World J Gastroenterol 2013; 19 (41) 6969-6978
    CrossrefPubMedGoogle Scholar
  • 25 Carr RM, Patel RT, Rao V. et al. Reduction of TIP47 improves hepatic steatosis and glucose homeostasis in mice. Am J Physiol Regul Integr Comp Physiol 2012; 302 (08) R996-R1003
    CrossrefPubMedGoogle Scholar
  • 26 Carr RM, Peralta G, Yin X, Ahima RS. Absence of perilipin 2 prevents hepatic steatosis, glucose intolerance and ceramide accumulation in alcohol-fed mice. PLoS One 2014; 9 (05) e97118
    CrossrefPubMedGoogle Scholar
  • 27 Varela GM, Antwi DA, Dhir R. et al. Inhibition of ADRP prevents diet-induced insulin resistance. Am J Physiol Gastrointest Liver Physiol 2008; 295 (03) G621-G628
    CrossrefPubMedGoogle Scholar
  • 28 Verweij N, Haas ME, Nielsen JB. et al. Germline Mutations in CIDEB and Protection against Liver Disease. N Engl J Med 2022; 387 (04) 332-344
    CrossrefPubMedGoogle Scholar
  • 29 Li JZ, Ye J, Xue B. et al. Cideb regulates diet-induced obesity, liver steatosis, and insulin sensitivity by controlling lipogenesis and fatty acid oxidation. Diabetes 2007; 56 (10) 2523-2532
    CrossrefPubMedGoogle Scholar
  • 30 Mashek DG, Khan SA, Sathyanarayan A, Ploeger JM, Franklin MP. Hepatic lipid droplet biology: getting to the root of fatty liver. Hepatology 2015; 62 (03) 964-967
    CrossrefPubMedGoogle Scholar
  • 31 Farese Jr RV, Walther TC. Lipid droplets finally get a little R-E-S-P-E-C-T. Cell 2009; 139 (05) 855-860
    CrossrefPubMedGoogle Scholar
  • 32 Tandra S, Yeh MM, Brunt EM. et al. Presence and significance of microvesicular steatosis in nonalcoholic fatty liver disease. J Hepatol 2011; 55 (03) 654-659
    CrossrefPubMedGoogle Scholar
  • 33 Goh GB, McCullough AJ. Natural history of nonalcoholic fatty liver disease. Dig Dis Sci 2016; 61 (05) 1226-1233
    CrossrefPubMedGoogle Scholar
  • 34 Scorletti E, Carr RM. A new perspective on NAFLD: Focusing on lipid droplets. J Hepatol 2022; 76 (04) 934-945
    CrossrefPubMedGoogle Scholar
  • 35 Zhang XQ, Xu CF, Yu CH, Chen WX, Li YM. Role of endoplasmic reticulum stress in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol 2014; 20 (07) 1768-1776
    CrossrefPubMedGoogle Scholar
  • 36 Ben M'barek K, Ajjaji D, Chorlay A, Vanni S, Forêt L, Thiam AR. ER Membrane phospholipids and surface tension control cellular lipid droplet formation. Dev Cell 2017; 41 (06) 591.e7-604.e7
    CrossrefPubMedGoogle Scholar
  • 37 Song MJ, Malhi H. The unfolded protein response and hepatic lipid metabolism in non alcoholic fatty liver disease. Pharmacol Ther 2019; 203: 107401
    CrossrefPubMedGoogle Scholar
  • 38 Lebeaupin C, Vallée D, Hazari Y, Hetz C, Chevet E, Bailly-Maitre B. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J Hepatol 2018; 69 (04) 927-947
    CrossrefPubMedGoogle Scholar
  • 39 Straub BK, Stoeffel P, Heid H, Zimbelmann R, Schirmacher P. Differential pattern of lipid droplet-associated proteins and de novo perilipin expression in hepatocyte steatogenesis. Hepatology 2008; 47 (06) 1936-1946
    CrossrefPubMedGoogle Scholar
  • 40 Ju L, Han J, Zhang X. et al. Obesity-associated inflammation triggers an autophagy-lysosomal response in adipocytes and causes degradation of perilipin 1. Cell Death Dis 2019; 10 (02) 121
    CrossrefPubMedGoogle Scholar
  • 41 Carr RM, Dhir R, Mahadev K, Comerford M, Chalasani NP, Ahima RS. Perilipin staining distinguishes between steatosis and nonalcoholic steatohepatitis in adults and children. Clin Gastroenterol Hepatol 2017; 15 (01) 145-147
    CrossrefPubMedGoogle Scholar
  • 42 Carr RM, Ahima RS. Pathophysiology of lipid droplet proteins in liver diseases. Exp Cell Res 2016; 340 (02) 187-192
    CrossrefPubMedGoogle Scholar
  • 43 Carr RM, Dhir R, Yin X, Agarwal B, Ahima RS. Temporal effects of ethanol consumption on energy homeostasis, hepatic steatosis, and insulin sensitivity in mice. Alcohol Clin Exp Res 2013; 37 (07) 1091-1099
    CrossrefPubMedGoogle Scholar
  • 44 McManaman JL, Bales ES, Orlicky DJ. et al. Perilipin-2-null mice are protected against diet-induced obesity, adipose inflammation, and fatty liver disease. J Lipid Res 2013; 54 (05) 1346-1359
    CrossrefPubMedGoogle Scholar
  • 45 Libby AE, Bales E, Orlicky DJ, McManaman JL. Perilipin-2 deletion impairs hepatic lipid accumulation by interfering with sterol regulatory element-binding protein (SREBP) activation and altering the hepatic lipidome. J Biol Chem 2016; 291 (46) 24231-24246
    CrossrefPubMedGoogle Scholar
  • 46 Faulkner CS, White CM, Shah VH, Jophlin LL. A single nucleotide polymorphism of PLIN2 is associated with nonalcoholic steatohepatitis and causes phenotypic changes in hepatocyte lipid droplets: a pilot study. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865 (05) 158637
    CrossrefPubMedGoogle Scholar
  • 47 Sentinelli F, Capoccia D, Incani M. et al. The perilipin 2 (PLIN2) gene Ser251Pro missense mutation is associated with reduced insulin secretion and increased insulin sensitivity in Italian obese subjects. Diabetes Metab Res Rev 2016; 32 (06) 550-556
    CrossrefPubMedGoogle Scholar
  • 48 Magné J, Aminoff A, Perman Sundelin J. et al. The minor allele of the missense polymorphism Ser251Pro in perilipin 2 (PLIN2) disrupts an α-helix, affects lipolysis, and is associated with reduced plasma triglyceride concentration in humans. FASEB J 2013; 27 (08) 3090-3099
    CrossrefPubMedGoogle Scholar
  • 49 Scorletti E, Vujkovic M, Himes B. et al. PLIN2 rs35568725 POLYMORPHISM AND NON-ALCOHOLIC FATTY LIVER DISEASE: A PHEWAS ANALYSIS. Hepatology 2022; 76: S872
    PubMedGoogle Scholar
  • 50 Nimura S, Yamaguchi T, Ueda K. et al. Olanzapine promotes the accumulation of lipid droplets and the expression of multiple perilipins in human adipocytes. Biochem Biophys Res Commun 2015; 467 (04) 906-912
    CrossrefPubMedGoogle Scholar
  • 51 Sztalryd C, Brasaemle DL. The perilipin family of lipid droplet proteins: gatekeepers of intracellular lipolysis. Biochim Biophys Acta Mol Cell Biol Lipids 2017; 1862 (10, Pt B): 1221-1232
    CrossrefPubMedGoogle Scholar
  • 52 Wang C, Zhao Y, Gao X. et al. Perilipin 5 improves hepatic lipotoxicity by inhibiting lipolysis. Hepatology 2015; 61 (03) 870-882
    CrossrefPubMedGoogle Scholar
  • 53 Asimakopoulou A, Engel KM, Gassler N. et al. Deletion of perilipin 5 protects against hepatic injury in nonalcoholic fatty liver disease via missing inflammasome activation. Cells 2020; 9 (06) 9
    CrossrefPubMedGoogle Scholar
  • 54 Ma SY, Sun KS, Zhang M. et al. Disruption of Plin5 degradation by CMA causes lipid homeostasis imbalance in NAFLD. Liver Int 2020; 40 (10) 2427-2438
    CrossrefPubMedGoogle Scholar
  • 55 Keenan SN, Meex RC, Lo JCY. et al. Perilipin 5 deletion in hepatocytes remodels lipid metabolism and causes hepatic insulin resistance in mice. Diabetes 2019; 68 (03) 543-555
    CrossrefPubMedGoogle Scholar
  • 56 Vujkovic M, Ramdas S, Lorenz KM. et al; Regeneron Genetics Center, Geisinger-Regeneron DiscovEHR Collaboration, EPoS Consortium, VA Million Veteran Program. A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation. Nat Genet 2022; 54 (06) 761-771
    CrossrefPubMedGoogle Scholar
  • 57 Bruschi FV, Claudel T, Tardelli M. et al. The PNPLA3 I148M variant modulates the fibrogenic phenotype of human hepatic stellate cells. Hepatology 2017; 65 (06) 1875-1890
    CrossrefPubMedGoogle Scholar
  • 58 Romeo S, Kozlitina J, Xing C. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40 (12) 1461-1465
    CrossrefPubMedGoogle Scholar
  • 59 Luukkonen PK, Nick A, Hölttä-Vuori M. et al. Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids. JCI Insight 2019; 4 (16) 4
    CrossrefPubMedGoogle Scholar
  • 60 Verkade HJ, Fast DG, Rusiñol AE, Scraba DG, Vance DE. Impaired biosynthesis of phosphatidylcholine causes a decrease in the number of very low density lipoprotein particles in the Golgi but not in the endoplasmic reticulum of rat liver. J Biol Chem 1993; 268 (33) 24990-24996
    CrossrefPubMedGoogle Scholar
  • 61 Li Z, Agellon LB, Allen TM. et al. The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis. Cell Metab 2006; 3 (05) 321-331
    CrossrefPubMedGoogle Scholar
  • 62 Abul-Husn NS, Cheng X, Li AH. et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N Engl J Med 2018; 378 (12) 1096-1106
    CrossrefPubMedGoogle Scholar
  • 63 Luukkonen PK, Tukiainen T, Juuti A. et al. Hydroxysteroid 17-β dehydrogenase 13 variant increases phospholipids and protects against fibrosis in nonalcoholic fatty liver disease. JCI Insight 2020; 5 (05) 5
    CrossrefPubMedGoogle Scholar
  • 64 Li X, Ye J, Zhou L, Gu W, Fisher EA, Li P. Opposing roles of cell death-inducing DFF45-like effector B and perilipin 2 in controlling hepatic VLDL lipidation. J Lipid Res 2012; 53 (09) 1877-1889
    CrossrefPubMedGoogle Scholar
  • 65 Xu W, Wu L, Yu M. et al. Differential roles of cell death-inducing DNA fragmentation factor-α-like effector (CIDE) proteins in promoting lipid droplet fusion and growth in subpopulations of hepatocytes. J Biol Chem 2016; 291 (09) 4282-4293
    CrossrefPubMedGoogle Scholar
  • 66 Ye J, Li JZ, Liu Y. et al. Cideb, an ER- and lipid droplet-associated protein, mediates VLDL lipidation and maturation by interacting with apolipoprotein B. Cell Metab 2009; 9 (02) 177-190
    CrossrefPubMedGoogle Scholar
  • 67 Brunt EM, Kleiner DE, Wilson LA, Belt P, Neuschwander-Tetri BA. NASH Clinical Research Network (CRN). Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology 2011; 53 (03) 810-820
    CrossrefPubMedGoogle Scholar
  • 68 Argo CK, Ikura Y, Lackner C, Caldwell SH. The fat droplet in hepatocellular ballooning and implications for scoring nonalcoholic steatohepatitis therapeutic response. Hepatology 2016; 63 (03) 1056-1057
    CrossrefPubMedGoogle Scholar
  • 69 Fujii H, Ikura Y, Arimoto J. et al. Expression of perilipin and adipophilin in nonalcoholic fatty liver disease; relevance to oxidative injury and hepatocyte ballooning. J Atheroscler Thromb 2009; 16 (06) 893-901
    CrossrefPubMedGoogle Scholar
  • 70 Caldwell S, Ikura Y, Dias D. et al. Hepatocellular ballooning in NASH. J Hepatol 2010; 53 (04) 719-723
    CrossrefPubMedGoogle Scholar
  • 71 Marra F, Svegliati-Baroni G. Lipotoxicity and the gut-liver axis in NASH pathogenesis. J Hepatol 2018; 68 (02) 280-295
    CrossrefPubMedGoogle Scholar
  • 72 Malhi H, Bronk SF, Werneburg NW, Gores GJ. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J Biol Chem 2006; 281 (17) 12093-12101
    CrossrefPubMedGoogle Scholar
  • 73 Gan LT, Van Rooyen DM, Koina ME, McCuskey RS, Teoh NC, Farrell GC. Hepatocyte free cholesterol lipotoxicity results from JNK1-mediated mitochondrial injury and is HMGB1 and TLR4-dependent. J Hepatol 2014; 61 (06) 1376-1384
    CrossrefPubMedGoogle Scholar
  • 74 Hager L, Li L, Pun H. et al. Lecithin:cholesterol acyltransferase deficiency protects against cholesterol-induced hepatic endoplasmic reticulum stress in mice. J Biol Chem 2012; 287 (24) 20755-20768
    CrossrefPubMedGoogle Scholar
  • 75 Francque S, Verrijken A, Mertens I. et al. Noncirrhotic human nonalcoholic fatty liver disease induces portal hypertension in relation to the histological degree of steatosis. Eur J Gastroenterol Hepatol 2010; 22 (12) 1449-1457
    PubMedGoogle Scholar
  • 76 Loneker AE, Alisafaei F, Kant A. et al. Lipid droplets are intracellular mechanical stressors that impair hepatocyte function. Proc Natl Acad Sci U S A 2023; 120 (16) e2216811120
    CrossrefPubMedGoogle Scholar
  • 77 DeLeve LD. Vascular liver disease and the liver sinusoidal endothelial cell. In: DeLeve LD, Garcia-Tsao G. eds. Vascular Liver Disease: Mechanisms and Management. New York, NY: Springer New York; 2011: 25-40
    CrossrefGoogle Scholar
  • 78 Corpechot C, Barbu V, Wendum D. et al. Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis. Hepatology 2002; 35 (05) 1010-1021
    CrossrefPubMedGoogle Scholar
  • 79 Seifalian AM, Piasecki C, Agarwal A, Davidson BR. The effect of graded steatosis on flow in the hepatic parenchymal microcirculation. Transplantation 1999; 68 (06) 780-784
    CrossrefPubMedGoogle Scholar
  • 80 Francque S, Wamutu S, Chatterjee S. et al. Non-alcoholic steatohepatitis induces non-fibrosis-related portal hypertension associated with splanchnic vasodilation and signs of a hyperdynamic circulation in vitro and in vivo in a rat model. Liver Int 2010; 30 (03) 365-375
    CrossrefPubMedGoogle Scholar
  • 81 Farrell GC, Teoh NC, McCuskey RS. Hepatic microcirculation in fatty liver disease. Anat Rec (Hoboken) 2008; 291 (06) 684-692
    CrossrefPubMedGoogle Scholar
  • 82 Rockey DC, Bell PD, Hill JA. Fibrosis–a common pathway to organ injury and failure. N Engl J Med 2015; 373 (01) 96
    PubMedGoogle Scholar
  • 83 Sung KC, Wild SH, Byrne CD. Resolution of fatty liver and risk of incident diabetes. J Clin Endocrinol Metab 2013; 98 (09) 3637-3643
    CrossrefPubMedGoogle Scholar
  • 84 Meyersohn NM, Mayrhofer T, Corey KE. et al. Association of hepatic steatosis with major adverse cardiovascular events, independent of coronary artery disease. Clin Gastroenterol Hepatol 2021; 19 (07) 1480-1488.e14
    CrossrefPubMedGoogle Scholar
  • 85 Chambergo-Michilot D, Rodrigo-Gallardo PK, Huaman MR, Vasquez-Chavesta AZ, Salinas-Sedo G, Toro-Huamanchumo CJ. Hypertension and histopathology severity of non-alcoholic fatty liver disease among adults with obesity: a cross-sectional study. Clin Exp Gastroenterol 2023; 16: 129-136
    CrossrefPubMedGoogle Scholar
  • 86 Chin Y, Lim J, Kong G. et al. Hepatic steatosis and advanced hepatic fibrosis are independent predictors of long-term mortality in acute myocardial infarction. Diabetes Obes Metab 2023; 25 (04) 1032-1044
    CrossrefPubMedGoogle Scholar
  • 87 Spitzer AL, Lao OB, Dick AA. et al. The biopsied donor liver: incorporating macrosteatosis into high-risk donor assessment. Liver Transpl 2010; 16 (07) 874-884
    CrossrefPubMedGoogle Scholar
  • 88 Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatol 2019; 70 (01) 151-171
    CrossrefPubMedGoogle Scholar
  • 89 Cheemerla S, Balakrishnan M. Global epidemiology of chronic liver disease. Clin Liver Dis (Hoboken) 2021; 17 (05) 365-370
    CrossrefPubMedGoogle Scholar
  • 90 Jeon S, Carr R. Alcohol effects on hepatic lipid metabolism. J Lipid Res 2020; 61 (04) 470-479
    CrossrefPubMedGoogle Scholar
  • 91 Schulze RJ, Ding WX. Lipid droplet dynamics in alcoholic fatty liver disease. Liver Res 2019; 3 (3–4): 185-190
    CrossrefPubMedGoogle Scholar
  • 92 Jeong WI, Osei-Hyiaman D, Park O. et al. Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver. Cell Metab 2008; 7 (03) 227-235
    CrossrefPubMedGoogle Scholar
  • 93 Esfandiari F, Medici V, Wong DH. et al. Epigenetic regulation of hepatic endoplasmic reticulum stress pathways in the ethanol-fed cystathionine beta synthase-deficient mouse. Hepatology 2010; 51 (03) 932-941
    CrossrefPubMedGoogle Scholar
  • 94 Dara L, Ji C, Kaplowitz N. The contribution of endoplasmic reticulum stress to liver diseases. Hepatology 2011; 53 (05) 1752-1763
    CrossrefPubMedGoogle Scholar
  • 95 Peng Z, Borea PA, Varani K. et al. Adenosine signaling contributes to ethanol-induced fatty liver in mice. J Clin Invest 2009; 119 (03) 582-594
    CrossrefPubMedGoogle Scholar
  • 96 You M, Matsumoto M, Pacold CM, Cho WK, Crabb DW. The role of AMP-activated protein kinase in the action of ethanol in the liver. Gastroenterology 2004; 127 (06) 1798-1808
    CrossrefPubMedGoogle Scholar
  • 97 You M, Liang X, Ajmo JM, Ness GC. Involvement of mammalian sirtuin 1 in the action of ethanol in the liver. Am J Physiol Gastrointest Liver Physiol 2008; 294 (04) G892-G898
    CrossrefPubMedGoogle Scholar
  • 98 Horiguchi N, Wang L, Mukhopadhyay P. et al. Cell type-dependent pro- and anti-inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury. Gastroenterology 2008; 134 (04) 1148-1158
    CrossrefPubMedGoogle Scholar
  • 99 Liangpunsakul S, Ross RA, Crabb DW. Activation of carbohydrate response element-binding protein by ethanol. J Investig Med 2013; 61 (02) 270-277
    CrossrefPubMedGoogle Scholar
  • 100 Marmier S, Dentin R, Daujat-Chavanieu M. et al. Novel role for carbohydrate responsive element binding protein in the control of ethanol metabolism and susceptibility to binge drinking. Hepatology 2015; 62 (04) 1086-1100
    CrossrefPubMedGoogle Scholar
  • 101 Zhang W, Sun Q, Zhong W, Sun X, Zhou Z. Hepatic peroxisome proliferator-activated receptor gamma signaling contributes to alcohol-induced hepatic steatosis and inflammation in mice. Alcohol Clin Exp Res 2016; 40 (05) 988-999
    CrossrefPubMedGoogle Scholar
  • 102 Addolorato G, Capristo E, Greco AV, Stefanini GF, Gasbarrini G. Energy expenditure, substrate oxidation, and body composition in subjects with chronic alcoholism: new findings from metabolic assessment. Alcohol Clin Exp Res 1997; 21 (06) 962-967
    PubMedGoogle Scholar
  • 103 Carr RM, Correnti J. Insulin resistance in clinical and experimental alcoholic liver disease. Ann N Y Acad Sci 2015; 1353 (01) 1-20
    CrossrefPubMedGoogle Scholar
  • 104 Hussain MM, Maxfield FR, Más-Oliva J. et al. Clearance of chylomicron remnants by the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor. J Biol Chem 1991; 266 (21) 13936-13940
    CrossrefPubMedGoogle Scholar
  • 105 Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 2005; 115 (05) 1343-1351
    CrossrefPubMedGoogle Scholar
  • 106 Mathur M, Yeh YT, Arya RK. et al. Adipose lipolysis is important for ethanol to induce fatty liver in the National Institute on Alcohol Abuse and Alcoholism murine model of chronic and binge ethanol feeding. Hepatology 2023; 77 (05) 1688-1701
    CrossrefPubMedGoogle Scholar
  • 107 Stahl A, Gimeno RE, Tartaglia LA, Lodish HF. Fatty acid transport proteins: a current view of a growing family. Trends Endocrinol Metab 2001; 12 (06) 266-273
    CrossrefPubMedGoogle Scholar
  • 108 Zhou J, Febbraio M, Wada T. et al. Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. Gastroenterology 2008; 134 (02) 556-567
    CrossrefPubMedGoogle Scholar
  • 109 Clugston RD, Yuen JJ, Hu Y. et al. CD36-deficient mice are resistant to alcohol- and high-carbohydrate-induced hepatic steatosis. J Lipid Res 2014; 55 (02) 239-246
    CrossrefPubMedGoogle Scholar
  • 110 Blomstrand R, Kager L, Lantto O. Studies on the ethanol-induced decrease of fatty acid oxidation in rat and human liver slices. Life Sci 1973; 13 (08) 1131-1141
    CrossrefPubMedGoogle Scholar
  • 111 Cederbaum AI, Lieber CS, Beattie DS, Rubin E. Effect of chronic ethanol ingestion on fatty acid oxidation by hepatic mitochondria. J Biol Chem 1975; 250 (13) 5122-5129
    CrossrefPubMedGoogle Scholar
  • 112 Hoek JB, Cahill A, Pastorino JG. Alcohol and mitochondria: a dysfunctional relationship. Gastroenterology 2002; 122 (07) 2049-2063
    CrossrefPubMedGoogle Scholar
  • 113 Correnti JM, Gottshall L, Lin A. et al. Ethanol and C2 ceramide activate fatty acid oxidation in human hepatoma cells. Sci Rep 2018; 8 (01) 12923
    CrossrefPubMedGoogle Scholar
  • 114 Suter PM, Schutz Y, Jequier E. The effect of ethanol on fat storage in healthy subjects. N Engl J Med 1992; 326 (15) 983-987
    CrossrefPubMedGoogle Scholar
  • 115 Sonko BJ, Prentice AM, Murgatroyd PR, Goldberg GR, van de Ven ML, Coward WA. Effect of alcohol on postmeal fat storage. Am J Clin Nutr 1994; 59 (03) 619-625
    CrossrefPubMedGoogle Scholar
  • 116 Sugimoto T, Yamashita S, Ishigami M. et al. Decreased microsomal triglyceride transfer protein activity contributes to initiation of alcoholic liver steatosis in rats. J Hepatol 2002; 36 (02) 157-162
    CrossrefPubMedGoogle Scholar
  • 117 Nanji AA, Dannenberg AJ, Jokelainen K, Bass NM. Alcoholic liver injury in the rat is associated with reduced expression of peroxisome proliferator-alpha (PPARalpha)-regulated genes and is ameliorated by PPARalpha activation. J Pharmacol Exp Ther 2004; 310 (01) 417-424
    CrossrefPubMedGoogle Scholar
  • 118 Kharbanda KK, Mailliard ME, Baldwin CR, Beckenhauer HC, Sorrell MF, Tuma DJ. Betaine attenuates alcoholic steatosis by restoring phosphatidylcholine generation via the phosphatidylethanolamine methyltransferase pathway. J Hepatol 2007; 46 (02) 314-321
    CrossrefPubMedGoogle Scholar
  • 119 Schulze RJ, Rasineni K, Weller SG. et al. Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7. Hepatol Commun 2017; 1 (02) 140-152
    CrossrefPubMedGoogle Scholar
  • 120 Chao X, Wang S, Zhao K. et al. Impaired TFEB-mediated lysosome biogenesis and autophagy promote chronic ethanol-induced liver injury and steatosis in mice. Gastroenterology 2018; 155 (03) 865.e12-879.e12
    CrossrefPubMedGoogle Scholar
  • 121 Thomes PG, Trambly CS, Fox HS, Tuma DJ, Donohue Jr TM. Acute and chronic ethanol administration differentially modulate hepatic autophagy and transcription factor EB. Alcohol Clin Exp Res 2015; 39 (12) 2354-2363
    CrossrefPubMedGoogle Scholar
  • 122 Rasineni K, Donohue Jr TM, Thomes PG. et al. Ethanol-induced steatosis involves impairment of lipophagy, associated with reduced Dynamin2 activity. Hepatol Commun 2017; 1 (06) 501-512
    CrossrefPubMedGoogle Scholar
  • 123 Jambunathan S, Yin J, Khan W, Tamori Y, Puri V. FSP27 promotes lipid droplet clustering and then fusion to regulate triglyceride accumulation. PLoS One 2011; 6 (12) e28614
    CrossrefPubMedGoogle Scholar
  • 124 Xu MJ, Cai Y, Wang H. et al. Fat-specific protein 27/CIDEC promotes development of alcoholic steatohepatitis in mice and humans. Gastroenterology 2015; 149 (04) 1030.e6-1041.e6
    PubMedGoogle Scholar
  • 125 Gu Y, Yang Y, Cao X. et al. Plin3 protects against alcoholic liver injury by facilitating lipid export from the endoplasmic reticulum. J Cell Biochem 2019; 120 (09) 16075-16087
    CrossrefPubMedGoogle Scholar
  • 126 Groebner JL, Girón-Bravo MT, Rothberg ML, Adhikari R, Tuma DJ, Tuma PL. Alcohol-induced microtubule acetylation leads to the accumulation of large, immobile lipid droplets. Am J Physiol Gastrointest Liver Physiol 2019; 317 (04) G373-G386
    CrossrefPubMedGoogle Scholar
  • 127 Buch S, Stickel F, Trépo E. et al. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis. Nat Genet 2015; 47 (12) 1443-1448
    CrossrefPubMedGoogle Scholar
  • 128 Bianco C, Casirati E, Malvestiti F, Valenti L. Genetic predisposition similarities between NASH and ASH: identification of new therapeutic targets. JHEP Rep Innov Hepatol 2021; 3 (03) 100284
    CrossrefPubMedGoogle Scholar
  • 129 Li JZ, Huang Y, Karaman R. et al. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J Clin Invest 2012; 122 (11) 4130-4144
    CrossrefPubMedGoogle Scholar
  • 130 Teo K, Abeysekera KWM, Adams L. et al; EU-PNAFLD Investigators, GOLD Consortium. rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: a meta-analysis. J Hepatol 2021; 74 (01) 20-30
    CrossrefPubMedGoogle Scholar
  • 131 Stickel F, Lutz P, Buch S. et al. Genetic variation in HSD17B13 reduces the risk of developing cirrhosis and hepatocellular carcinoma in alcohol misusers. Hepatology 2020; 72 (01) 88-102
    CrossrefPubMedGoogle Scholar
  • 132 Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology 2013; 57 (04) 1333-1342
    CrossrefPubMedGoogle Scholar
  • 133 Ferguson D, Zhang J, Davis MA. et al. The lipid droplet-associated protein perilipin 3 facilitates hepatitis C virus-driven hepatic steatosis. J Lipid Res 2017; 58 (02) 420-432
    CrossrefPubMedGoogle Scholar
  • 134 [Anonymous]. Global progress report on HIV, viral hepatitis and sexually transmitted infections, 2021. In: Accountability for the global health sector strategies 2016–2021: actions for impact. Geneva: World Health Organization; 2021
    Google Scholar
  • 135 Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology 2001; 33 (06) 1358-1364
    CrossrefPubMedGoogle Scholar
  • 136 André P, Komurian-Pradel F, Deforges S. et al. Characterization of low- and very-low-density hepatitis C virus RNA-containing particles. J Virol 2002; 76 (14) 6919-6928
    CrossrefPubMedGoogle Scholar
  • 137 Niepmann M. Hepatitis C virus RNA translation. Curr Top Microbiol Immunol 2013; 369: 143-166
    PubMedGoogle Scholar
  • 138 McLauchlan J, Lemberg MK, Hope G, Martoglio B. Intramembrane proteolysis promotes trafficking of hepatitis C virus core protein to lipid droplets. EMBO J 2002; 21 (15) 3980-3988
    CrossrefPubMedGoogle Scholar
  • 139 Boulant S, Montserret R, Hope RG. et al. Structural determinants that target the hepatitis C virus core protein to lipid droplets. J Biol Chem 2006; 281 (31) 22236-22247
    CrossrefPubMedGoogle Scholar
  • 140 Pène V, Hernandez C, Vauloup-Fellous C, Garaud-Aunis J, Rosenberg AR. Sequential processing of hepatitis C virus core protein by host cell signal peptidase and signal peptide peptidase: a reassessment. J Viral Hepat 2009; 16 (10) 705-715
    CrossrefPubMedGoogle Scholar
  • 141 Boulant S, Targett-Adams P, McLauchlan J. Disrupting the association of hepatitis C virus core protein with lipid droplets correlates with a loss in production of infectious virus. J Gen Virol 2007; 88 (Pt 8): 2204-2213
    CrossrefPubMedGoogle Scholar
  • 142 Miyanari Y, Atsuzawa K, Usuda N. et al. The lipid droplet is an important organelle for hepatitis C virus production. Nat Cell Biol 2007; 9 (09) 1089-1097
    CrossrefPubMedGoogle Scholar
  • 143 Bartenschlager R, Penin F, Lohmann V, André P. Assembly of infectious hepatitis C virus particles. Trends Microbiol 2011; 19 (02) 95-103
    CrossrefPubMedGoogle Scholar
  • 144 Sidorkiewicz M. Hepatitis C virus uses host lipids to its own advantage. Metabolites 2021; 11 (05) 11
    CrossrefPubMedGoogle Scholar
  • 145 Gastaminza P, Cheng G, Wieland S, Zhong J, Liao W, Chisari FV. Cellular determinants of hepatitis C virus assembly, maturation, degradation, and secretion. J Virol 2008; 82 (05) 2120-2129
    CrossrefPubMedGoogle Scholar
  • 146 Hueging K, Doepke M, Vieyres G. et al. Apolipoprotein E codetermines tissue tropism of hepatitis C virus and is crucial for viral cell-to-cell transmission by contributing to a postenvelopment step of assembly. J Virol 2014; 88 (03) 1433-1446
    CrossrefPubMedGoogle Scholar
  • 147 Lonardo A, Adinolfi LE, Restivo L. et al. Pathogenesis and significance of hepatitis C virus steatosis: an update on survival strategy of a successful pathogen. World J Gastroenterol 2014; 20 (23) 7089-7103
    CrossrefPubMedGoogle Scholar
  • 148 Hope RG, McLauchlan J. Sequence motifs required for lipid droplet association and protein stability are unique to the hepatitis C virus core protein. J Gen Virol 2000; 81 (Pt 8): 1913-1925
    CrossrefPubMedGoogle Scholar
  • 149 Loizides-Mangold U, Clément S, Alfonso-Garcia A. et al. HCV 3a core protein increases lipid droplet cholesteryl ester content via a mechanism dependent on sphingolipid biosynthesis. PLoS One 2014; 9 (12) e115309
    CrossrefPubMedGoogle Scholar
  • 150 Herker E, Harris C, Hernandez C. et al. Efficient hepatitis C virus particle formation requires diacylglycerol acyltransferase-1. Nat Med 2010; 16 (11) 1295-1298
    CrossrefPubMedGoogle Scholar
  • 151 Camus G, Herker E, Modi AA. et al. Diacylglycerol acyltransferase-1 localizes hepatitis C virus NS5A protein to lipid droplets and enhances NS5A interaction with the viral capsid core. J Biol Chem 2013; 288 (14) 9915-9923
    CrossrefPubMedGoogle Scholar
  • 152 Xu N, Zhang SO, Cole RA. et al. The FATP1-DGAT2 complex facilitates lipid droplet expansion at the ER-lipid droplet interface. J Cell Biol 2012; 198 (05) 895-911
    CrossrefPubMedGoogle Scholar
  • 153 Vieyres G, Pietschmann T. HCV pit stop at the lipid droplet: refuel lipids and put on a lipoprotein coat before exit. Cells 2019; 8 (03) 8
    CrossrefPubMedGoogle Scholar
  • 154 Lerat H, Kammoun HL, Hainault I. et al. Hepatitis C virus proteins induce lipogenesis and defective triglyceride secretion in transgenic mice. J Biol Chem 2009; 284 (48) 33466-33474
    CrossrefPubMedGoogle Scholar
  • 155 Lowey B, Hertz L, Chiu S. et al. Hepatitis C virus infection induces hepatic expression of NF-κB-inducing kinase and lipogenesis by downregulating miR-122. mBio 2019; 10 (04) e01617-e01619
    CrossrefPubMedGoogle Scholar
  • 156 Khatun M, Sur S, Steele R, Ray R, Ray RB. Inhibition of long noncoding RNA Linc-Pint by hepatitis C virus in infected hepatocytes enhances lipogenesis. Hepatology 2021; 74 (01) 41-54
    CrossrefPubMedGoogle Scholar
  • 157 Vieyres G, Reichert I, Carpentier A, Vondran FWR, Pietschmann T. The ATGL lipase cooperates with ABHD5 to mobilize lipids for hepatitis C virus assembly. PLoS Pathog 2020; 16 (06) e1008554
    CrossrefPubMedGoogle Scholar
  • 158 Carr RM, Dhir R, Mahadev K. et al. Perilipin staining distinguishes between steatosis and non-alcoholic steatohepatitis in adults and children. Clin Gastroenterol Hepatol 2017; 15 (01) 145-147
    CrossrefPubMedGoogle Scholar
  • 159 Zhang J, Gao X, Yuan Y. et al. Perilipin 5 alleviates HCV NS5A-induced lipotoxic injuries in liver. Lipids Health Dis 2019; 18 (01) 87
    CrossrefPubMedGoogle Scholar
  • 160 Salameh H, Masadeh M, Al Hanayneh M. et al. PNPLA3 polymorphism increases risk for and severity of chronic hepatitis C liver disease. World J Hepatol 2016; 8 (35) 1584-1592
    CrossrefPubMedGoogle Scholar
  • 161 About F, Abel L, Cobat A. HCV-associated liver fibrosis and HSD17B13. N Engl J Med 2018; 379 (19) 1875-1876
    CrossrefPubMedGoogle Scholar
  • 162 Burlone ME, Bellan M, Barbaglia MN. et al. HSD17B13 and other liver fat-modulating genes predict development of hepatocellular carcinoma among HCV-positive cirrhotics with and without viral clearance after DAA treatment. Clin J Gastroenterol 2022; 15 (02) 301-309
    CrossrefPubMedGoogle Scholar
  • 163 Listenberger LL, Brown DA. Fluorescent detection of lipid droplets and associated proteins. Curr Protoc Cell Biol 2007 ;Chapter 24:Unit 24.22
    PubMedGoogle Scholar
  • 164 Listenberger LL, Studer AM, Brown DA, Wolins NE. Fluorescent detection of lipid droplets and associated proteins. Curr Protoc Cell Biol 2016; 71: 31.1 , 14
    CrossrefPubMedGoogle Scholar
  • 165 Qiu B, Simon MC. BODIPY 493/503 staining of neutral lipid droplets for microscopy and quantification by flow cytometry. Bio Protoc 2016; 6 (17) 6
    PubMedGoogle Scholar
  • 166 Chen J, Yue F, Kuang S. Labeling and analyzing lipid droplets in mouse muscle stem cells. STAR Protoc 2022; 3 (04) 101849
    CrossrefPubMedGoogle Scholar
  • 167 Garcia K, Alves A, Ribeiro-Rodrigues TM, Reis F, Viana S. Analysis of fluorescent-stained lipid droplets with 3d reconstruction for hepatic steatosis assessment. J Vis Exp 2023; (196) e65206 DOI: 10.3791/65206.
    CrossrefPubMedGoogle Scholar
  • 168 Gojanovich AD, Gimenez MC, Masone D. et al. Human adipose-derived mesenchymal stem/stromal cells handling protocols. lipid droplets and proteins double-staining. Front Cell Dev Biol 2018; 6: 33
    CrossrefPubMedGoogle Scholar
  • 169 Nishad A, Naseem A, Rani S, Malik S. Automated qualitative batch measurement of lipid droplets in the liver of bird using ImageJ. STAR Protoc 2023; 4 (03) 102466
    CrossrefPubMedGoogle Scholar
  • 170 Liu CY, Zhu J, Xie Z. Visualizing yeast organelles with fluorescent protein markers. J Vis Exp 2022; (182) e63846 DOI: 10.3791/63846.
    CrossrefPubMedGoogle Scholar
  • 171 Galli A, Scheel TKH, Prentoe JC, Mikkelsen LS, Gottwein JM, Bukh J. Analysis of hepatitis C virus core/NS5A protein co-localization using novel cell culture systems expressing core-NS2 and NS5A of genotypes 1-7. J Gen Virol 2013; 94 (Pt 10): 2221-2235
    CrossrefPubMedGoogle Scholar
  • 172 Schüssele DS, Haller PK, Haas ML, Hunter C, Sporbeck K, Proikas-Cezanne T. Autophagy profiling in single cells with open source CellProfiler-based image analysis. Autophagy 2023; 19 (01) 338-351
    CrossrefPubMedGoogle Scholar
  • 173 Adomshick V, Pu Y, Veiga-Lopez A. Automated lipid droplet quantification system for phenotypic analysis of adipocytes using CellProfiler. Toxicol Mech Methods 2020; 30 (05) 378-387
    CrossrefPubMedGoogle Scholar
  • 174 Stiebing C, Schmölz L, Wallert M, Matthäus C, Lorkowski S, Popp J. Raman imaging of macrophages incubated with triglyceride-enriched oxLDL visualizes translocation of lipids between endocytic vesicles and lipid droplets. J Lipid Res 2017; 58 (05) 876-883
    CrossrefPubMedGoogle Scholar
  • 175 Fujimoto T, Ohsaki Y, Suzuki M, Cheng J. Imaging lipid droplets by electron microscopy. Methods Cell Biol 2013; 116: 227-251
    CrossrefPubMedGoogle Scholar
  • 176 Brasaemle DL, Wolins NE. Isolation of lipid droplets from cells by density gradient centrifugation. Curr Protoc Cell Biol 2016; 72: 3.15.1-3.15.13
    PubMedGoogle Scholar
  • 177 Ding Y, Zhang S, Yang L. et al. Isolating lipid droplets from multiple species. Nat Protoc 2013; 8 (01) 43-51
    CrossrefPubMedGoogle Scholar
  • 178 Mannik J, Meyers A, Dalhaimer P. Isolation of cellular lipid droplets: two purification techniques starting from yeast cells and human placentas. J Vis Exp 2014; (86) 50981 DOI: 10.3791/50981.
    CrossrefPubMedGoogle Scholar
  • 179 Brasaemle DL, Wolins NE. Isolation of lipid droplets from cells by density gradient centrifugation. Curr Protoc Cell Biol 2016; 72: 15.1 , 13
    CrossrefPubMedGoogle Scholar
  • 180 Rösch K, Kwiatkowski M, Schlüter H, Herker E. Lipid droplet isolation for quantitative mass spectrometry analysis. J Vis Exp 2017; (122) 55585
    PubMedGoogle Scholar
  • 181 Brettschneider J, Correnti JM, Lin C, Williams B, Oranu A, Kuriakose A, McIver-Jenkins D, Haba A, Kaneza I, Jeon S, Scorletti E, Carr RM. Rapid lipid droplet isolation protocol using a well-established organelle isolation kit. J Vis Exp 2019; (146) e59290 DOI: 10.3791/59290.
    CrossrefPubMedGoogle Scholar
  • 182 Kamerkar S, Singh J, Tripathy S, Bhonsle H, Kumar M, Mallik R. Metabolic and immune-sensitive contacts between lipid droplets and endoplasmic reticulum reconstituted in vitro. Proc Natl Acad Sci U S A 2022; 119 (24) e2200513119
    CrossrefPubMedGoogle Scholar
  • 183 Preuss C, Jelenik T, Bódis K. et al. A new targeted lipidomics approach reveals lipid droplets in liver, muscle and heart as a repository for diacylglycerol and ceramide species in non-alcoholic fatty liver. Cells 2019; 8 (03) 8
    CrossrefPubMedGoogle Scholar
  • 184 Rémy C, Fouilhé N, Barba I. et al. Evidence that mobile lipids detected in rat brain glioma by 1H nuclear magnetic resonance correspond to lipid droplets. Cancer Res 1997; 57 (03) 407-414
    PubMedGoogle Scholar
  • 185 Bartz R, Li WH, Venables B. et al. Lipidomics reveals that adiposomes store ether lipids and mediate phospholipid traffic. J Lipid Res 2007; 48 (04) 837-847
    CrossrefPubMedGoogle Scholar
  • 186 Nigam S, Ranjan R, Sinha N, Ateeq B. Nuclear magnetic resonance spectroscopy reveals dysregulation of monounsaturated fatty acid metabolism upon SPINK1 attenuation in colorectal cancer. NMR Biomed 2022; 35 (07) e4705
    CrossrefPubMedGoogle Scholar
  • 187 Schmidt C, Ploier B, Koch B, Daum G. Analysis of yeast lipid droplet proteome and lipidome. Methods Cell Biol 2013; 116: 15-37
    CrossrefPubMedGoogle Scholar
  • 188 Lagrutta LC, Layerenza JP, Bronsoms S, Trejo SA, Ves-Losada A. Nuclear-lipid-droplet proteome: carboxylesterase as a nuclear lipase involved in lipid-droplet homeostasis. Heliyon 2021; 7 (03) e06539
    CrossrefPubMedGoogle Scholar
  • 189 Peterson CWH, Deol KK, To M, Olzmann JA. Optimized protocol for the identification of lipid droplet proteomes using proximity labeling proteomics in cultured human cells. STAR Protoc 2021; 2 (02) 100579
    CrossrefPubMedGoogle Scholar
  • 190 Tatenaka Y, Kato H, Ishiyama M. et al. Monitoring lipid droplet dynamics in living cells by using fluorescent probes. Biochemistry 2019; 58 (06) 499-503
    CrossrefPubMedGoogle Scholar
  • 191 Ma X, Zhi Z, Zhang S, Liu P. Measurement of ATGL activity using adiposomes. Biophys Rep 2023; 9 (01) 3-14
    CrossrefPubMedGoogle Scholar
  • 192 Bridge-Comer PE, Reilly SM. Measuring the rate of lipolysis in ex vivo murine adipose tissue and primary preadipocytes differentiated in vitro. J Vis Exp 2023; (193) e65106 DOI: 10.3791/65106.
    CrossrefPubMedGoogle Scholar
  • 193 Chorlay A, Santinho A, Thiam AR. Making droplet-embedded vesicles to model cellular lipid droplets. STAR Protoc 2020; 1 (03) 100116
    CrossrefPubMedGoogle Scholar
  • 194 Zhi Z, Ma X, Zhou C, Mechler A, Zhang S, Liu P. Protocol for using artificial lipid droplets to study the binding affinity of lipid droplet-associated proteins. STAR Protoc 2022; 3 (01) 101214
    CrossrefPubMedGoogle Scholar
  • 195 Drew L. Drug development: sprint finish. Nature 2017; 551 (7681) 551
    CrossrefPubMedGoogle Scholar
  • 196 A study to assess safety, tolerability, PK and PD of AZD2693 in non-alcoholic steatohepatitis patients. Accessed September 25, 2023, at: https://clinicaltrials.gov/ct2/show/NCT04483947
    PubMedGoogle Scholar
  • 197 Lindén D, Ahnmark A, Pingitore P. et al. Pnpla3 silencing with antisense oligonucleotides ameliorates nonalcoholic steatohepatitis and fibrosis in Pnpla3 I148M knock-in mice. Mol Metab 2019; 22: 49-61
    CrossrefPubMedGoogle Scholar
  • 198 Knockdown of HSD17B13 mRNA, pharmacokinetics, safety, and tolerability, of AZD7503 in non-alcoholic fatty liver disease. Accessed September 25, 2023, at: https://clinicaltrials.gov/ct2/show/NCT05560607
    PubMedGoogle Scholar