OR05-5 Hepatic role of TSH in the control of triglyceride synthesis through PPAR/SREBP1c pathway

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR05-Lipids: Regulation & Mechanism of Disease
Saturday, June 15, 2013: 11:30 AM-1:00 PM
Presentation Start Time: 12:30 PM
Room 133 (Moscone Center)
Fang Yan*1, Jiajun Zhao2, Ling Gao2, Chao Xu3, Haiqing Zhang4, Chunxiao Yu4 and Yongfeng Song5
1Provincial Hospital Affiliated to ShanDong University, Endo, 2Shandong Provincial Hosp, Jinan Shandong, 3Shandong Institute of Endocrinol, Jinan, Shandong, 4Shandong Provincial Hospital, Endo, 5Shandong Provincial Hospital, Endo, Jinan, Shandong Province

Subclinical hypothyroidism (SCH) has been associated with increased plasmic triglyceride (TG) in recent clinical studies, but these reports are controversial. Up to date, it is unclear for the underlying mechanism of this association. Our previous study has found TSH receptors exist in the hepatocytes. Here we focused on TSH, which is elevated in serum of SCH, to explore the effect of TSH on TG synthesis in the liver.


We firstly set up Tshr-/- and Tshr +/+ mouse models, and tested in vivo if there was difference of liver TG contents and the expression of the lipogenic gene and protein using oil-red O staining, real-time PCR, western-blotting, immunohistochemistry and immunofluorescence, respectively. Next, we chosed HepG2 cells, which was widely used in hepatocytic research, as a model in vitro. After treating the cells with TSH or PPARα agonist in the presence or absence of PPARα antagonist, we observed that TSH played direct effects on a panel of molecules relative to TG synthesis such as SREBP1c, a main regulator of triglyceride synthesis.


(1)         Compared with the control littermate (Tshr+/+), the liver TG content of Tshr-/- (supplemented with T4) mice declined to 52.6% (p < 0.05), accompanied with a decrease in the expression of nuclei PPARα and mature SREBP1c (48.9% and 71.1% vs. control, respectively, both p < 0.05). It suggests that the changes depends on liver TSH receptor.

(2)         TSH induced dose- and time-dependent increase in the levels of PPARα, SREBP1c as well as their downstream molecules in HepG2 cells. Compared to the control, the levels of PPARα and SREBP1c were elevated by approximately 1 fold, respectively (both p < 0.05) when 4μM TSH treated for 48h. Similarly, double-immunofluorescence showed that TSH stimulated stronger fluorescence of both PPARα and SREBP1c in the nuclei and plasma. As a consequence, intracellular TG elevated 21.7% (p< 0.05) relative to control, which was reconfirmed by oil-red O staining.

(3)         The PPARα agonist, fenofibrate, increased the hepatocytic expression of mature SREBP1c protein in dose- and time-dependent manners. 100 μM fenofibrate for 48h triggered mature SREBP1c protein a 3.5-fold increase of the control (p< 0.05).

(4)         When PPARα was immunoprecipitated, endogenous SREBP-1c mature protein was present in the complex with PPARα. SREBP-1c was also detected in reciprocal coimmunoprecipitation of PPARα. That implies there exist a direct intercombine between PPARα and SREBP1c proteins.

(5)         When treatment of MK886 to block PPARα activation prior to TSH, the TSH-inducing changes above were inversed, and showed the decreased expression of the activated PPARα, SREBP-1c mature form as well as intercellular TG content.  It suggests that PPARα mediated the TG synthetic role of TSH by direct interaction with SREBP1c mature protein.


TSH increases the TG content in liver cells through PPARα/SREBP1c signaling pathway.

Nothing to Disclose: FY, JZ, LG, CX, HZ, CY, YS

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This work was supported by grants from the National Basic Research Program (2012CB524900), the National Natural Science Foundation (30971409)