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Thyroid Hormone Deficiency Modifies Hepatic Lipid Droplet Morphology and Molecular Properties in Lithogenic-Diet Supplemented MiceFunding: The authors were financially supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – ZW221/2–1 and Project-ID 424957847 - TRR 296/1.
Objective Thyroid hormones have been associated with a hepatic lipid lowering effect and thyroid function has been shown to play a substantial role in development of non-alcoholic fatty liver disease. Hepatic lipid droplets differ in the number, size and molecular properties depending on metabolic state or pathological condition. However, in how far thyroid hormone deficiency affects hepatic lipid droplet morphology and molecular properties is still poorly understood. Therefore, we performed a study in mice using a lithogenic diet model of steatohepatitis and modulated the thyroid hormone status.
Methods Male and female three months old C57BL/6 mice were divided into a euthyroid (control), a lithogenic (litho) and a lithogenic+thyroid hormone deficient (litho+hypo) group and treated for six weeks. Hepatic transmission electron microscopy and gene expression analysis of lipid-droplet associated proteins were performed.
Results Increased mean diameters of hepatic lipid droplets and a shift towards raised electron-density in lipid droplets was observed under thyroid hormone deficiency. Furthermore thyroid hormone deficiency altered hepatic expression of genes involved in lipophagy and triacylglycerol mobilization. Interestingly, while the impact of thyroid hormone deficiency on lipid droplet morphology seems to be sex-independent, hepatic lipid droplet-associated gene expression differed significantly between both sexes.
Conclusion This study demonstrates that thyroid hormone deficiency alters hepatic lipid droplet morphology and hepatic gene expression of lipid droplet-associated proteins in a lithogenic diet mouse model of steatohepatitis.
Key wordsthyroid dysfunction - lipid droplets - hepatocytes - hepatic lipid accumulation - metabolic liver diseases
Received: 18 January 2021
Received: 22 February 2021
Accepted: 03 March 2021
28 May 2021 (online)
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- 1 Grasselli E, Voci A, Demori I. et al. Triglyceride mobilization from lipid droplets sustains the anti-steatotic action of iodothyronines in cultured rat hepatocytes. Front Physiol 2016; 6: 418
- 2 Thiam AR, Farese RV, Walther TC. The biophysics and cell biology of lipid droplets. Nat Rev Mol Cell Biol 2013; 14: 775-786
- 3 Natarajan SK, Rasineni K, Ganesan M. et al. Structure, function and metabolism of hepatic and adipose tissue lipid droplets: Implications in alcoholic liver disease. Current Molecular Pharmacology 2017; 10: 237-248
- 4 Murphy S, Martin S, Parton RG. Lipid droplet-organelle interactions; sharing the fats. Mol Biol Cell 2009; 1791: 441-447
- 5 Kiss RS, Nilsson T. Rab proteins implicated in lipid storage and mobilization. J Biomed Res 2014; 28: 169-177
- 6 Crunk AE, Monks J, Murakami A. et al. Dynamic regulation of hepatic lipid droplet properties by diet. PLoS One 2013; 8: e67631-e67631
- 7 Lee J, Ha J, Jo K. et al. Male-specific association between subclinical hypothyroidism and the risk of non-alcoholic fatty liver disease estimated by hepatic steatosis index: Korea National Health and Nutrition Examination Survey 2013 to 2015. Sci Rep 2018; 8: 15145
- 8 Kube I, Tardio LB, Hofmann U. et al. Hypothyroidism increases cholesterol gallstone prevalence in mice by elevated hydrophobicity of primary bile acids. Thyroid 2020; DOI: 10.1089/thy.2020.0636.
- 9 Schwertheim S, Westerwick D, Jastrow H. et al. Intranuclear inclusions in hepatocellular carcinoma contain autophagy-associated proteins and correlate with prolonged survival. J Pathol Clin Res 2019; 5: 164-176
- 10 Zwanziger D, Rakov H, Engels K. et al. Sex-Dependent Claudin-1 Expression in the Liver of Euthyroid and Hypothyroid Mice. Eur Thyroid J 2015; 4: 67-73
- 11 Hodges BDM, Wu CC. Proteomic insights into an expanded cellular role for cytoplasmic lipid droplets. J Lipid Res 2010; 51: 262-273
- 12 Egan CE, Daugherity EK, Rogers AB. et al. CCR2 and CD44 promote inflammatory cell recruitment during fatty liver formation in a lithogenic diet fed mouse model. PLoS One 2013; 8: e65247
- 13 Eshraghian A, Hamidian Jahromi A. Non-alcoholic fatty liver disease and thyroid dysfunction: a systematic review. World J Gastroenterol 2014; 20: 8102-8109
- 14 Zhang E, Najt CP, Hu H. et al. Hepatic perilipin 5 promotes lipophagy and alters lipid droplet and mitochondrial dynamics. FASEB J 2019; 33: 490.19-490.19
- 15 Grasselli E, Voci A, Demori I. et al. 3,5-Diiodo-l-thyronine modulates the expression of genes of lipid metabolism in a rat model of fatty liver. J Endocrinol 2012; 212: 149-158
- 16 Yau WW, Singh BK, Lesmana R. et al. Thyroid hormone (T3) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy. Autophagy 2019; 15: 131-150
- 17 Martin-Montalvo A, Sun Y, Diaz-Ruiz A. et al. Cytochrome b5 reductase and the control of lipid metabolism and healthspan. NPJ Aging Mech Dis 2016; 2: 16006
- 18 Ducharme NA, Bickel PE. Minireview: Lipid droplets in lipogenesis and lipolysis. Endocrinology 2008; 149: 942-949
- 19 Deng Y, Zhou C, Hammad MA. Rab18 Binds PLIN2 and ACSL3 to Mediate Lipid Droplet Dynamics. bioRxiv 2020; 2020.05.02.073957