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AIMS/HYPOTHESIS: Non-alcoholic fatty liver disease (NAFLD) associated with type 2 diabetes may more easily progress towards severe forms of non-alcoholic steatohepatitis (NASH) and cirrhosis. Although the Wnt effector transcription factor 7-like 2 (TCF7L2) is closely associated with type 2 diabetes risk, the role of TCF7L2 in NAFLD development remains unclear. Here, we investigated how changes in TCF7L2 expression in the liver affects hepatic lipid metabolism based on the major risk factors of NAFLD development.

METHODS

Tcf7l2 was selectively ablated in the liver of C57BL/6N mice by inducing the albumin (Alb) promoter to recombine Tcf7l2 alleles floxed at exon 5 (liver-specific Tcf7l2-knockout [KO] mice: Alb-Cre;Tcf7l2). Alb-Cre;Tcf7l2 and their wild-type (Tcf7l2) littermates were fed a high-fat diet (HFD) or a high-carbohydrate diet (HCD) for 22 weeks to reproduce NAFLD/NASH. Mice were refed a standard chow diet or an HCD to stimulate de novo lipogenesis (DNL) or fed an HFD to provide exogenous fatty acids. We analysed glucose and insulin sensitivity, metabolic respiration, mRNA expression profiles, hepatic triglyceride (TG), hepatic DNL, selected hepatic metabolites, selected plasma metabolites and liver histology.

RESULTS

Alb-Cre;Tcf7l2 essentially exhibited increased lipogenic genes, but there were no changes in hepatic lipid content in mice fed a normal chow diet. However, following 22 weeks of diet-induced NAFLD/NASH conditions, liver steatosis was exacerbated owing to preferential metabolism of carbohydrate over fat. Indeed, hepatic Tcf7l2 deficiency enhanced liver lipid content in a manner that was dependent on the duration and amount of exposure to carbohydrates, owing to cell-autonomous increases in hepatic DNL. Mechanistically, TCF7L2 regulated the transcriptional activity of Mlxipl (also known as ChREBP) by modulating O-GlcNAcylation and protein content of carbohydrate response element binding protein (ChREBP), and targeted Srebf1 (also called SREBP1) via miRNA (miR)-33-5p in hepatocytes. Eventually, restoring TCF7L2 expression at the physiological level in the liver of Alb-Cre;Tcf7l2 mice alleviated liver steatosis without altering body composition under both acute and chronic HCD conditions.

CONCLUSIONS/INTERPRETATION: In mice, loss of hepatic Tcf7l2 contributes to liver steatosis by inducing preferential metabolism of carbohydrates via DNL activation. Therefore, TCF7L2 could be a promising regulator of the NAFLD associated with high-carbohydrate diets and diabetes since TCF7L2 deficiency may lead to development of NAFLD by promoting utilisation of excess glucose pools through activating DNL.

DATA AVAILABILITY

RNA-sequencing data have been deposited into the NCBI GEO under the accession number GSE162449 ( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE162449 ).

目的/假设：与 2 型糖尿病相关的非酒精性脂肪性肝病（NAFLD）可能更容易向非酒精性脂肪性肝炎（NASH）和肝硬化等严重形式发展。虽然 Wnt 效应因子转录因子 7 样 2（TCF7L2）与 2 型糖尿病风险密切相关，但 TCF7L2 在 NAFLD 发病机制中的作用仍不清楚。在这里，我们研究了肝脏中 TCF7L2 表达的变化如何影响肝内脂质代谢，这是基于 NAFLD 发展的主要危险因素。

方法

通过诱导白蛋白（Alb）启动子使 Tcf7l2 基因在第 5 外显子处发生重组，在 C57BL/6N 小鼠中选择性地敲除肝 Tcf7l2（肝特异性 Tcf7l2 敲除 [KO] 小鼠：Alb-Cre；Tcf7l2）。Alb-Cre；Tcf7l2 和其野生型（Tcf7l2）同窝仔鼠分别用高脂肪饮食（HFD）或高碳水化合物饮食（HCD）喂养 22 周，以复制 NAFLD/NASH。将小鼠重新喂食标准饲料或 HCD 以刺激从头合成脂肪（DNL），或喂食 HFD 以提供外源性脂肪酸。我们分析了葡萄糖和胰岛素敏感性、代谢呼吸、mRNA 表达谱、肝甘油三酯（TG）、肝 DNL、选定的肝代谢物、选定的血浆代谢物和肝组织学。

结果

Alb-Cre；Tcf7l2 肝脏中脂生成基因明显增加，但正常饮食喂养的小鼠肝内脂质含量没有变化。然而，在 22 周的饮食诱导的 NAFLD/NASH 条件下，由于优先代谢碳水化合物而不是脂肪，肝脂肪变性加剧。事实上，肝 Tcf7l2 缺失以依赖于暴露于碳水化合物的持续时间和量的方式增强肝脂质含量，这是由于肝内 DNL 的细胞自主增加所致。机制上，TCF7L2 通过调节 O-连接糖基化和碳水化合物反应元件结合蛋白（ChREBP）的蛋白含量，调节 Mlxipl（也称为 ChREBP）的转录活性，在肝细胞中通过 miRNA（miR）-33-5p 靶向 Srebf1（也称为 SREBP1）。最终，在 Alb-Cre；在 HCD 条件下，无论是急性还是慢性，通过恢复 Tcf7l2 在肝脏中的生理水平，都可以减轻肝脂肪变性，而不改变身体成分。

结论/解释：在小鼠中，肝 Tcf7l2 的缺失通过诱导 DNL 激活导致优先代谢碳水化合物，从而导致肝脂肪变性。因此，TCF7L2 可能是一种有前途的与高碳水化合物饮食和糖尿病相关的 NAFLD 调节剂，因为 TCF7L2 缺失可能通过激活 DNL 利用过多的葡萄糖池来促进 NAFLD 的发展。