Glycogen storage disease type Ia (GSD Ia) is an inborn error of metabolism caused by
defective glucose-6-phosphatase (G6PC) activity. GSD Ia patients exhibit severe
hepatomegaly due to glycogen and triglyceride (TG) accumulation in the liver. We have
previously shown that the activity of Carbohydrate Response Element Binding Protein
(ChREBP), a key regulator of glycolysis and de novo lipogenesis, is increased in GSD Ia.
the current study we assessed the contribution of ChREBP to non-alcoholic fatty liver disease (NAFLD) development in a mouse model for hepatic GSD Ia. Liver-specific G6pc knockout (L-G6pc-/-) mice were treated with AAV2/8-shChREBP to normalize hepatic
ChREBP activity to levels observed in wildtype (L-G6pc+/+) mice receiving AAV8-shScramble.
Hepatic ChREBP knockdown markedly increased liver weight and hepatocyte size in L-G6pc
/- mice. This was associated with hepatic accumulation of G6P, glycogen and lipids, while the
expression of glycolytic and lipogenic genes was reduced. Enzyme activities, flux
measurements, hepatic metabolite analysis and VLDL-TG secretion assays revealed that
hepatic ChREBP knockdown reduced downstream glycolysis and de novo lipogenesis, but
also strongly suppressed hepatic VLDL lipidation hence promoting the storage of ‘old fat’.
Interestingly, enhanced VLDL-TG secretion in shScramble-treated L-G6pc-/- mice associated
with a ChREBP-dependent induction of the VLDL lipidation proteins MTTP and TM6SF2, the latter being confirmed by ChIP-PCR.
Conclusion: Attenuation of hepatic ChREBP induction in GSD Ia liver aggravates hepatomegaly due to further accumulation of glycogen and lipids
as a result of reduced glycolysis and suppressed VLDL-TG secretion. TM6SF2, critical for
VLDL formation, was identified as a novel ChREBP target in mouse liver. Altogether, our
data show that enhanced ChREBP activity limits NAFLD development in GSD Ia by balancing hepatic TG production and -secretion.
Hepatology: Hepatic ChREBP activation limits NAFLD development in a mouse model for Glycogen Storage Disease type Ia
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