Effects of UBE3A on Cell and Liver Metabolism through the Ubiquitination of PDHA1 and ACAT1

Nonalcoholic fatty liver disease (NAFLD) is substantiated
by the
reprogramming of liver metabolic pathways that disrupts the homeostasis
of lipid and glucose metabolism and thus promotes the progression
of the disease. The metabolic pathways associated with NAFLD are regulated
at different levels from gene transcription to various post-translational
modifications including ubiquitination. Here, we used a novel orthogonal
ubiquitin transfer platform to identify pyruvate dehydrogenase A1
(PDHA1) and acetyl-CoA acetyltransferase 1 (ACAT1), two important
enzymes that regulate glycolysis and ketogenesis, as substrates of
E3 ubiquitin ligase UBE3A/E6AP. We found that overexpression of UBE3A
accelerated the degradation of PDHA1 and promoted glycolytic activities
in HEK293 cells. Furthermore, a high-fat diet suppressed the expression
of UBE3A in the mouse liver, which was associated with increased ACAT1
protein levels, while forced expression of UBE3A in the mouse liver
resulted in decreased ACAT1 protein contents. As a result, the mice
with forced expression of UBE3A in the liver exhibited enhanced accumulation
of triglycerides, cholesterol, and ketone bodies. These results reveal
the role of UBE3A in NAFLD development by inducing the degradation
of ACAT1 in the liver and promoting lipid storage. Overall, our work
uncovers an important mechanism underlying the regulation of glycolysis
and lipid metabolism through UBE3A-mediated ubiquitination of PDHA1
and ACAT1 to regulate their stabilities and enzymatic activities in
the cell.