TAK1 regulates hepatic lipid homeostasis through SREBP

Abstract

Sterol regulatory element-binding proteins (SREBPs) are key transcription factors regulating cholesterol and fatty acid biosynthesis. SREBP activity is tightly regulated to maintain lipid homeostasis, and is modulated upon extracellular stimuli such as growth factors. While the homeostatic SREBP regulation is well studied, stimuli-dependent regulatory mechanisms are still elusive. Here we demonstrate that SREBPs are regulated by a previously uncharacterized mechanism through TGF-β activated kinase 1 (TAK1), a signaling molecule of inflammation. We found that TAK1 binds to and inhibits mature forms of SREBPs. In an in vivo setting, hepatocyte-specific Tak1 deletion upregulates liver lipid deposition and lipogenic enzymes in the mouse model. Furthermore, hepatic Tak1 deficiency causes steatosis pathologies including elevated blood triglyceride and cholesterol levels, which are established risk factors for the development of hepatocellular carcinoma (HCC) and are indeed correlated with Tak1-deficiency-induced HCC development. Pharmacological inhibition of SREBPs alleviated the steatosis and reduced the expression level of the HCC marker gene in the Tak1-deficient liver. Thus, TAK1 regulation of SREBP critically contributes to the maintenance of liver homeostasis to prevent steatosis, which is a potentially important mechanism to prevent HCC development.

USP18 protects against hepatic steatosis and insulin resistance through its deubiquitinating activity

“…We here found that the deteriorating effects of USP18 knockout on hepatic steatosis and insulin resistance in HFD mice can be abolished by reducing TAK1 activation with its inhibitor. On the contrary, other studies found that disruption of TAK1 exacerbates lipid metabolic disorders and causes tumorigenesis in hepatocytes . The underlying reasons for these conflicting results are still unknown.…”

“…On the contrary, other studies found that disruption of TAK1 exacerbates lipid metabolic disorders and causes tumorigenesis in hepatocytes. (38)(39)(40) The underlying reasons for these conflicting results are still unknown. It is possible that TAK1 plays essential roles in various physiological and pathological processes and that both total ablation and hyperactivation of TAK1 can induce severe hepatic injuries.…”

Hepatocyte DUSP14 maintains metabolic homeostasis and suppresses inflammation in the liver

“…(29) Furthermore, our results showed that suppressing TAK1 activation with a specific inhibitor ameliorated insulin resistance, hepatic steatosis, and inflammation in mice fed a HFD diet, highlighting the causal role of TAK1 hyperactivation in glucolipid metabolic dysfunction in the liver. Intriguingly, other studies have verified an essential role of TAK1 in maintaining functional homeostasis of the liver, as indicated by exacerbated lipid metabolic disorders (30) and hepatic tumorigenesis (31) in TAK1-HKO mice. This inconsistency may be due to the diverse functionality of TAK1 in basal physiological processes.…”

Noncanonical cell death program independent of caspase activation cascade and necroptotic modules is elicited by loss of TGFβ-activated kinase 1

“…The activation of these downstream signaling factors produces cytokines while maintaining cell viability and lipid metabolism during inflammation 21, 22 . TAK1, similar to caspases and RIPK3, is known to be targeted and inhibited by pathogens 23 .…”