Novel function for endosomal trafficking adaptors in hepatic metabolic disease

In recent years, membrane trafficking through the endosomal transport system has received increasing attention for the regulation of metabolism. Quick responses of metabolically active tissues such as the liver to alterations in the nutrient status are highly dependent on the timely shuttling of transporters and growth-hormone receptors to the plasma membrane. Moreover, in highly polarized cells – as are hepatocytes –, transport and secretion of proteins occurs under an additional level of complexity, where certain proteins are required at apical (biliary) membranes while other proteins must be delivered to basolateral (sinusoidal) membranes. Bridging the two fields of endocytosis and liver metabolism is therefore an important step towards a better understanding of metabolic associated liver disease.

Here, we are reporting a thus far unknown role for an endocytic membrane trafficking adaptor protein in NASH development and progression. We found our protein to be upregulated in livers of various mouse models of NASH, as well as in human NASH patients. Interestingly, protein levels are correlating positively with degree of fibrosis in mice fed a NASH-inducing diet. When depleted of this protein, livers of mice fed two different NASH-inducing diets show increased fibrosis, compared to control mice. Using several proteomics approaches, we are currently investigating potential cargo proteins to dissect the underlying mechanism of enhanced disease progression.

Taken together, our data indicate a novel trafficking route regulating NASH disease progression. As hampering with this route seems to worsen disease outcome, we are hoping to identify mechanisms that could possibly improve disease outcome if increased.

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Publication History

Article published online:
26 January 2022