非酒精性脂肪肝病係指一種脂肪堆積在肝臟中的疾病。攝取過多的養份，如：西式飲食習慣，是一種導致非酒精性脂肪肝病發生的常見危險因子。在動物研究中，高脂飲食廣泛地用來誘發脂肪肝的產生。最近，我們發現餵食高脂飼料之後，會誘發老鼠產生脂肪肝以及增加血清皮脂酮濃度。皮質酮是一種嚙齒類中主要的醣皮質類固醇。此外，通過對老鼠雙邊腎上腺摘除手術能降低皮質酮濃度並有效減緩高脂飲食所引發的脂肪肝。據此，我們假設高脂飲食所導致的血清皮質酮濃度上升參與在高脂飼料誘發脂肪肝的進程中。L/ L小鼠，是一種在膽固醇側鏈解離酶基因的啟動子序列中，類固醇生成因子1結合位有突變的老鼠，能夠在不影響基礎皮質醇分泌的狀況下，抑止經由刺激所誘發的皮質醇分泌。實驗動物在12週的高脂飲食後，由高脂飲食所增加的血清皮脂酮以及脂肪肝都被L/ L突變所抑止。此外，在回補皮質酮到高脂飲食的L/ L小鼠後，能夠反轉L/ L突變對於脂肪肝的影響。接著我們探討皮質醇參與在高脂飲食所導致之脂肪肝的機制。我們發現肝臟中的CD36表現量，一種脂肪酸轉位酶，主要負責細胞對脂肪的攝取，在高脂飲食之後會增加，且在雙邊腎上腺摘除手術之後減少。而高脂飲食增加的脂肪酸轉位酶表現量能夠被L/ L突變所阻止，且回補皮質酮到高脂飲食的L/ L小鼠便能增加其脂肪酸轉位酶表現量。我們還發現皮脂酮能夠直接增加小鼠肝臟的脂肪酸轉位酶表現量。據此，我們認為由高脂飲食所增加的血清皮質酮參與脂肪肝的發生，並且是透過提升肝臟脂肪酸移位酶的表現量。

關鍵詞：高脂飲食；皮質酮；非酒精性脂肪肝；脂肪酸移位酶；類固醇生成

Nonalcoholic fatty liver disease (NAFLD) is a condition in which fat builds up in liver. Excessive nutrient, e.g. western pattern diet, is a common risk factor for NAFLD. In animal study, high-fat diet (HFD) is a widely used method to induce NAFLD. Recently, we found that mice fed with HFD had fatty liver and increased levels of corticosterone (CORT), the major glucocorticoid in rodents. Furthermore, reducing CORT by bilateral adrenalectomy (ADX) attenuated the HFD-induced fatty liver in mice. Accordingly, I hypothesize that HFD-induced increase of CORT contributes to the development of fatty liver in mice. The L/L mice, which have a mutated binding sequence for steroidogenic factor-1 on the promoter region of the Cyp11a1 gene that attenuates the stimulation-induced release of CORT without affecting the basal secretion of CORT. After 12-week HFD feeding, results showed that both the HFD-induced increases of CORT and fatty liver was blunted by L/L mutation. Besides, supplement of CORT reversed the L/L mutation effect in L/L-HFD mice. Next, we investigated the underlying mechanism for the involvement of CORT in the HFD-induced fatty liver. initially, we found the expression of hepatic CD36, a fatty acid translocase governing the uptake of lipid, was increased by HFD, and decreased after ADX surgery. Then, the HFD-induced CD36 was blunted by L/L mutation. And supplement of CORT increased the CD36 in L/L-HFD mice. In addition, we also found that CORT directly upregulated hepatic CD36 in mice. In conclusion, HFD-induced fatty liver is caused by increased plasma levels of CORT and upregulation of hepatic CD36.

Keywords: high-fat diet, corticosterone, NAFLD, CD36, steroidogenesis

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