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The Role of Hepatic CIDEC/Fsp27 in Triglyceride Homeostasis and Metabolic Disorders
Başlık:
The Role of Hepatic CIDEC/Fsp27 in Triglyceride Homeostasis and Metabolic Disorders
Yazar:
Rajamoorthi, Ananthi, author.
ISBN:
9780438128057
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (159 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-11(E), Section: B.
Advisors: Angel Baldan Committee members: David A. Ford; Jane McHowat; Brent A. Neuschwander-Tetri.
Özet:
For my doctoral dissertation I investigated the functional roles of a lipid droplet-associated protein, CIDEC/Fsp27, in hepatocellular lipid metabolism. I further tested the therapeutic potential of targeting Fsp27 in non-alcoholic fatty liver disease and atherosclerosis. We had previously shown that acute knockdown of Fsp27 and PPAR-alpha activation promote the turnover of triglycerides (TAGs) in primary hepatocytes and synergistically reduce hepatic TAGs in chow-fed mice. I subsequently tested the therapeutic potential of a combined therapy (ASO-Fsp27 and fenofibrate, a PPAR-alpha agonist) in a diet-induced mouse model of steatohepatitis. The combined therapy not only reduced visceral adiposity but ameliorated hepatic steatosis, inflammation and fibrosis. Interestingly, silencing Fsp27 alone significantly reduced circulating very low-density lipoprotein (VLDL). To test whether hepatic CIDEC/Fsp27 may regulate the secretion of TAG-rich lipoproteins and further investigate the functional roles of liver-specific Fsp27 in triglyceride metabolism, I generated a knockout mouse model in which Fsp27 was deleted in the hepatocyte. Characterization of these mice showed that hepatic Fsp27 not only promotes triglyceride storage and lipid droplet growth under different nutritional conditions, but regulates glycogen synthesis, mitochondrial biogenesis and VLDL-TAG secretion in the liver. To test whether the effects of targeting Fsp27 on hypertriglyceridemia and visceral adiposity would in turn ameliorate the progression of atherosclerosis, I chronically silenced Fsp27 in an atheroprone mouse model. Anti-Fsp27 oligos not only prevented diet-induced hypertriglyceridemia and promoted browning of white adipose tissue, but significantly reduced atherosclerotic lesions in low-density lipoprotein (LDL) receptor knockout mice. These data not only introduce novel functional roles for hepatic CIDEC/Fsp27 in regulating lipid and carbohydrate homeostasis in the liver, but provide further therapeutic options to treat patients with metabolic syndrome and reduce risk of cardiovascular diseases.
Notlar:
School code: 0193
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(694144.1) | 694144-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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