Liver ChREBP Protects Against Fructose-Induced Glycogenic Hepatotoxicity by Regulating L-Type Pyruvate Kinase

Abstract

Excessive fructose consumption is closely linked to the pathogenesis of metabolic disease. Carbohydrate response element-binding protein (ChREBP) is a transcription factor essential for fructose tolerance in mice. However, the functional significance of liver ChREBP in fructose metabolism remains unclear. Here, we show that liver ChREBP protects mice against fructose-induced hepatotoxicity by regulating liver glycogen metabolism and ATP homeostasis. Liver-specific ablation of ChREBP did not compromise fructose tolerance, but rather caused severe transaminitis and hepatomegaly with massive glycogen overload in mice fed a high-fructose diet, while no obvious inflammation, cell death, or fibrosis was detected in the liver. In addition, liver ATP contents were significantly decreased by ChREBP deficiency in the fed state, which was rendered more pronounced by fructose feeding. Mechanistically, liver contents of glucose-6-phosphate (G6P), an allosteric activator of glycogen synthase, were markedly increased in the absence of liver ChREBP, while fasting-induced glycogen breakdown was not compromised. Furthermore, hepatic overexpression of LPK, a ChREBP target gene in glycolysis, could effectively rescue glycogen overload and ATP reduction, as well as mitigate fructose-induced hepatotoxicity in ChREBP-deficient mice. Taken together, our findings establish a critical role of liver ChREBP in coping with hepatic fructose stress and protecting from hepatotoxicity by regulating LPK.

The Protective Role of the Carbohydrate Response Element Binding Protein in the Liver: The Metabolite Perspective

“…This was supported by raised liver cholesterol levels in a global-ChREBP -/model and lowering of cholesterol by ChREBP overexpression (53). However in LiChREBP -/models on high-fructose diets, liver cholesterol was either decreased or unchanged despite raised ALAT (17,54,55). Raised hepatic cholesterol in global-ChREBP -/-(53), may be linked to endotoxemia consequent to intestinal dysfunction and inflammation as was observed in intestinal-ChREBP -/mice (17).…”

“…A further hypothesis is that ChREBP attenuates accumulation of hepatic triglycerides and diacylglycerides by promoting triglyceride secretion (54,56,57). However, the raised ALAT in the LiChREBP -/did not associate with raised liver triglycerides or diacylglycerides (17,(54)(55)(56), implicating mechanisms other than cholesterol, triglyceride or diacylglyceride accumulation in the ChREBP-mediated protection.…”

“…Most of the studies using ChREBP knock-down models have provided evidence for a protective role for ChREBP in liver function (Figure 2), particularly during challenge with a fructosecontaining diet (52)(53)(54)(55)(56) or in other compromised metabolic states such as glucose 6-phosphatase deficiency (57). ChREBP knock-down studies have used either total ChREBP deletion (23,52,53,58) or liver-selective models generated by crossing ChREBP fl o x mice with albumin-Cre transgenic mice (LiChREBP -/-) (17,54,55) or by short-term ChREBP knockdown using antisense oligonucleotides (56) or shRNA with adenoviral vectors (57,59). While the focus of the earlier studies was on the liver, ChREBP is also important in the intestine (17) and in adipose tissue (60).…”

“…Studies on LiChREBP -/models from three independent groups have shown that during challenge with high-fructose or high-sucrose diets the ChREBP deficiency in liver associates with raised plasma alanine aminotransferase (ALAT) activity, a marker of hepatocyte damage, establishing a protective role for hepatic ChREBP in fructose metabolism (17,54,55). Various hypotheses can be considered for ChREBP-mediated protection from fructose-induced liver damage.…”

Zbtb20 deficiency causes cardiac contractile dysfunction in mice

“…mtDNA content was determined as previously described. 29 Briefly, we extracted total DNA from heart with a DNA MiNi Kit (#51304, QIAamp) following the operation manual guideline. mtDNA content was measured using real-time PCR for cytochrome c oxidase subunit 2 (COX2, one of the components of complex IV) or mitochondrially encoded NADH dehydrogenase-1 (mtND1), and normalized with β-actin gene as an internal control encoded by nuclear DNA.…”