The TAZ protein may play a role in metabolic adaptations to chronic cholestasis and may be important in Alagille syndrome (ALGS), according to a new study published in the FASED Journal. This may have potential implications for the clinical regulation of hypercholesterolemia and long-term liver health.

TAZ is a paralog of Yes-associated protein 1 (YAP1), the loss of which during early liver development has been shown to cause an ALGS-like phenotype in a mouse model. This includes the absence of intrahepatic bile ducts and severe cholestasis.

Here, a team of researchers led by Satdarshan P. Monga, MD, from the University of Pittsburgh in Pennsylvania investigated the relationship between YAP1 and TAZ after noticing that in the absence of YAP1, TAZ was significantly upregulated in hepatocytes.


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When they deleted the genes coding for both proteins during early liver development in the mice, the researchers saw that the animals either died in utero or were stillborn. However, they did not have any visible abnormalities or gross abnormalities in liver morphology, suggesting that they died due to a reason other than liver problems.

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Interestingly, when the researchers analyzed animals with no YAP1 that were heterozygous for TAZ, they saw that most males died during embryonic development, while females with 1 copy of TAZ had a phenotype similar to YAP1 knock-out mice. This included a complete lack of intrahepatic bile ducts leading to severe chronic cholestatic disease. Moreover, these animals had worse hepatocyte injury but the levels of hepatocyte proliferation were not affected.

“We also found significant elevation in serum cholesterol compared to YAP1 [knock-out] alone, and xanthomas were observed at later stages on these mice,” the researchers wrote, “suggesting worsening metabolic derangements caused by TAZ heterozygosity beyond what was observed in YAP1 [knock-out] alone.

There were no differences in bile acid profiles in both liver and serum in animals that were heterozygous for TAZ and those that were not. The researchers are continuing to investigate the potential role of TAZ in liver metabolic health.

Reference

Molina LM, Gabdulkhakova A, Zhu J, et al. In the absence of YAP, TAZ contributes to hepatocyte adaptation in chronic cholestasis in females. FASEB J. Published online May 13, 2022. doi:10.1096/fasebj.2022.36.S1.R3167