Tcf7l2 in hepatocytes regulates de novo lipogenesis in diet-induced non-alcoholic fatty liver disease in mice.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:36759348", "kind": "science-record", "revision": 4, "content_hash": "sha256:56c08c497260d5a651be612d0b75b91dbc100ce382281061ed42ec73340f907e", "created_at": "2026-11-01T19:01:19Z", "updated_at": "2026-11-01T22:51:12Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Tcf7l2 in hepatocytes regulates de novo lipogenesis in diet-induced non-alcoholic fatty liver disease in mice.", "doi": "10.1007/s00125-023-05878-8", "pmid": "36759348", "authors": ["Da Som Lee", "Tae Hyeon An", "Hyunmi Kim", "Eunsun Jung", "Gyeonghun Kim", "Seung Yeon Oh", "Jun Seok Kim", "Hye Jin Chun", "Jaeeun Jung", "Eun-Woo Lee", "Baek-Soo Han", "Dai Hoon Han", "Yong-Ho Lee", "Tae-Su Han", "Keun Hur", "Chul-Ho Lee", "Dae-Soo Kim", "Won Kon Kim", "Jun Won Park", "Seung-Hoi Koo", "Je Kyung Seong", "Sang Chul Lee", "Hail Kim", "Kwang-Hee Bae", "Kyoung-Jin Oh"], "journal": "Diabetologia", "year": 2023, "abstract": "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.\nMETHODS: 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;Tcf7l2f/f). Alb-Cre;Tcf7l2f/f and their wild-type (Tcf7l2f/f) 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.\nRESULTS: Alb-Cre;Tcf7l2f/f 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;Tcf7l2f/f mice alleviated liver steatosis without altering body composition under both acute and chronic HCD conditions.\nCONCLUSIONS/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.\nDATA 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 ).", "claims": [{"id": "claim-method", "statement": "Statistical differences between two experimental groups were evaluated by the two-tailed unpaired Student’s t test. One-way ANOVA with Tukey’s multiple comparison test was performed using GraphPad Prism 8.0.1 (GraphPad Software, USA) when comparing three or more groups, as reported in the figure legends.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:36759348", "locator": "sections[22] \"Statistical analysis\" paragraph 2", "quote": "Statistical differences between two experimental groups were evaluated by the two-tailed unpaired Student’s t test. One-way ANOVA with Tukey’s multiple comparison test was performed using GraphPad Prism 8.0.1 (GraphPad Software, USA) when comparing three or more groups, as reported in the figure legends."}], "state": "complete"}, {"id": "claim-data-access", "statement": "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). Data that support the findings of this study are available from the lead contact upon reasonable request.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:36759348", "locator": "sections[42] \"notes\" paragraph 1", "quote": "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). Data that support the findings of this study are available from the lead contact upon reasonable request."}], "state": "complete"}, {"id": "claim-target-result", "statement": "In mice, loss of hepatic Tcf7l2 contributes to liver steatosis by inducing preferential metabolism of carbohydrates via DNL activation.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:36759348", "locator": "sections[0] \"Abstract\" paragraph 4", "quote": "In mice, loss of hepatic Tcf7l2 contributes to liver steatosis by inducing preferential metabolism of carbohydrates via DNL activation."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "In mice, loss of hepatic Tcf7l2 contributes to liver steatosis by inducing preferential metabolism of carbohydrates via DNL activation.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:36759348"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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Mice were refed a standard chow diet or an HCD to stim", "ere were no changes in hepatic lipid content in mice fed a normal chow diet. However, following 2", "HCD conditions. CONCLUSIONS/INTERPRETATION: In mice, loss of hepatic Tcf7l2 contributes to liver"], "order_basis": "paper_text_order:57", "id": "assay:1"}, {"role": "data_generation", "definition_id": "rna_seq", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["s through activating DNL. 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