探討低溫刺激促進脂肪產熱過程中HLJ1所扮演之角色

Abstract

肥胖是現時公共衛生上一個嚴峻的議題，肥胖會使人營養不良，令身體出現代謝不平衡的問題。現代社會中人們患上肥胖症大多是由於後天因素影響，生活習慣絮亂、飲良習慣不健康都會導致肥胖症的發生。當吸取過量高脂肪性飲食或高熱量食物時，脂肪及熱量會儲存在白色脂肪細胞內。而減輕體重則可靠棕色脂肪組織會把脂肪消耗掉轉以熱量形式釋放（非顫抖式產熱）。非氈抖式產熱可能受外界環境影響，像是低溫環境可加強產熱，例如當大腦感受到寒冷時交感神經會釋放出去甲腎上腺素(norepinephrine)，其接觸脂肪細胞表面的受體後會活化產熱路徑，像是加快第一型解偶聯蛋白基因(Ucp1)轉錄，增加能量代謝及產熱。HLJ1是DNAJ/HSP40家族的一員，之前已被發現與肝臟脂肪代謝有關，缺乏HLJ1蛋白的小鼠會發展出脂肪肝的情況，在本篇研究中，我們發現HLJ1可能參與在脂肪組織中的產熱活化路徑。在室溫情況下，我們發現缺乏HLJ1的小鼠鼠蹊部白色脂肪(Inguinal White Adipose Tissue)油滴顆粒面積比野生型小鼠的大，且該小鼠負責主要脂肪酸合成的脂肪酸合成酶基因表現量顯著比野生型小鼠高但當小鼠接受低溫刺激七天後，小鼠鼠蹊部白色脂肪HLJ1表現量顯著增加，且缺乏HLJ1小鼠鼠蹊部白色脂肪外觀比野生型小鼠的更顯棕色、油滴顆粒表面積也明顯比較小。更重要的是，產熱標誌基因Ucp1在缺乏HLJ1的小鼠鼠蹊部白色脂肪中明顯上升，在一筆RNA定序的數據也得知該小鼠其他產熱基因表現也上升，代表缺乏HLJ1會增加白色脂肪之產熱能力，因此本研究認為HLJ1在產熱過程中扮演重要角色。

Obesity is a consequence of genetics factor, eating habits, and lifestyle habits-mediated energy imbalance. Body weight gains when energy intake exceeds energy expenditure over a period of time. It is reported that cold induced thermogenesis can re-establish energy balance via burning calories into heat by brown adipocytes or beige adipocytes, and hence ameliorate obesity. HLJ1, a member of DNAJ/Hsp40 co-chaperone, plays a crucial role in unfolded protein response (UPR) system and ER stress. Previously, our group demonstrated HLJ1 was up-regulated in cells with high fat medium treatment and mice deficient in HLJ1 developed impaired lipid metabolism in liver. Our microarray analysis gives us a hint of HLJ1 participating in adipose tissue thermogenesis under cold stress. Under room temperature, iWAT of HLJ1 knockout (KO) mice showed increased expression of Fatty Acid Synthase (Fasn), which meant the KO mice had upregulated adipogenesis. To see whether HLJ1 was involved in adaptive thermogenesis, C57BL/6 and HLJ1-KO mice were divided into either room temperature or cold groups. After one week of cold exposure, elevated thermogenesis and reduced lipid droplets surface were observed in HLJ1-KO mice iWAT compared to WT iWAT. HLJ1 was markedly increased in iWAT of WT mice after cold stress. Body weight of HLJ1-KO mice was obviously reduced and beige selective genes such as Ucp1, Cox7a1 and Cox8b expression was also obviously increased in KO mice iWAT after chronic cold exposure. Taken together, this study indicated that HLJ1 made a contribution in cold induced thermogenesis. It might develop as a potential therapeutic target to treat obesity.