Hsieh and Colleagues Report a New Role for Ttc39 in Regulating Liver Fat

November 28, 2016

In the absence of T39, LXR assembly into a multiprotein complex that conjugates it to ubiquitin moieties does not occur, and LXR is spared from proteasomal degradation. In enterocytes, the increase in LXRα/β protein upregulates Abca1 and promotes HDL production. In the liver, LXRα protein increase leads to the induction of Abcg5/8, which decreases dietary cholesterol uptake and increases cholesterol excretion, leading to cholesterol lowering. LXRα-mediated Insig2a prevents SREBP-1 processing in the fasted state, while Pcyt1a, and Cept1 induction increases microsomal membrane phosphatidylcholine content that continues to inhibit SREBP-1 processing in postprandial state. LPCAT3 induction resulted in increased incorporation of PUFA into phospholipid species which also contributed to the decrease in SREBP-1 processing. The decrease in nuclear SREBP-1 prevents the induction of lipogenic genes such as Fasn. Therefore, unlike the gene expression profile that arises from potent synthetic ligands, increasing endogenous LXRα protein levels preferentially upregulates cholesterol removal pathways while inhibiting lipogenesis.

Read the article: TTC39B deficiency stabilizes LXR reducing both atherosclerosis and steatohepatitis