Liver-Specific β-Catenin Knockout Mice Exhibit Defective Bile Acid and Cholesterol Homeostasis and Increased Susceptibility to Diet-Induced Steatohepatitis
Open accessAbstract
Although the role of Wnt/beta-catenin signaling in liver growth and development is well established, its contribution in non-neoplastic hepatic pathologies has not been investigated. Here, we examine the role of beta-catenin in a murine model of diet-induced liver injury. Mice with hepatocyte-specific beta-catenin deletion (KO) and littermate controls were fed the steatogenic methionine and choline-deficient (MCD) diet or the corresponding control diet for 2 weeks and characterized for histological, biochemical, and molecular changes. KO mice developed significantly higher steatohepatitis and fibrosis on the MCD diet compared with wild-type mice. Both wild-type and KO livers accumulated triglyceride on the MCD diet but, unexpectedly, higher hepatic cholesterol levels were observed in KO livers on both control and MCD diets. Gene expression analysis showed that hepatic cholesterol accumulation in KO livers was not attributable to increased synthesis or uptake. KO mice had lower expression of bile acid synthetic enzymes but exhibited higher hepatic bile acid and serum bilirubin levels, suggesting defects in bile export. Therefore, loss of beta-catenin in the liver leads to defective cholesterol and bile acid metabolism in the liver and increased susceptibility to developing steatohepatitis in the face of metabolic stress.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
RSPO3, LGR4/5 and their downstream target β-catenin protect against MASLD and ALD.
“By contrast, MASLD and ALD, against which RSPO3, LGR4/5 and their downstream target β-catenin protect35,39, represent the commonest forms of CLD and liver fibrosis in patients.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [35]
The Discussion (page not specified in our copy) reports that liver-specific β-catenin knockout mice developed more severe steatohepatitis on a methionine- and choline-deficient diet, suggesting a protective effect of β-catenin under metabolic stress. The paper does not establish protection by RSPO3 or LGR4/5, or protection against alcohol-associated liver disease (ALD); its mouse diet model does not establish protection against MASLD in patients. (LLM, conf=0.86)
Experimental — accuracy not yet measuredHSC-derived RSPO3 critically impacts liver size, zonation, metabolism, regeneration and injury.
“The critical impact of HSC-derived RSPO3 on liver size, zonation, metabolism, regeneration and injury matches findings in mice with hepatocyte-specific deletion of β-catenin or LGR4/524,25,34–39, rendering RSPO3–LGR4-mediated HSC–hepatocyte communication a gatekeeper of liver function in health and disease.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [35]
The paper’s opening summary describes hepatocyte-specific β-catenin knockout mice with altered cholesterol and bile-acid metabolism and greater diet-induced liver injury. The section “Levels of β-Catenin do not Change Significantly on the MCD Diet” also reports loss of a zone-3 marker in those mice. It does not establish matching effects on liver size or regeneration; the RSPO3 finding is the citing authors’ framing, not a finding attributed to this source. (LLM, conf=0.86)
Experimental — accuracy not yet measuredHSC-derived RSPO3, hepatocyte-expressed LGR4 and its downstream target β-catenin are central mediators of the HSC-hepatocyte cross-talk that controls liver size, zonation and function.
“Thus, Rspo3ΔHSC mice reproduced key aspects of HSC-depleted, Lgr4/Lgr5ΔHep and Ctnnb1ΔHep mice24,25,34–39, suggesting HSC-derived RSPO3, hepatocyte-expressed LGR4 and its downstream target β-catenin as central mediators of the HSC–hepatocyte cross-talk that controls liver size, zonation and function.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [35]
β-catenin has roles in hepatic bile acid metabolism as well as mitochondrial function and energy balance, which have been linked to increased steatosis and liver injury in mice with hepatocellular deletion of β-catenin signalling components and in non-hepatic tissues.
“These findings match the role of β-catenin in hepatic bile acid metabolism35,39,45 as well as mitochondrial function and energy balance37,38, which have been linked to increased steatosis and liver injury in mice with hepatocellular deletion of β-catenin signalling components35,37–39 and in non-hepatic tissues46,47.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [35]
The β-catenin-WNT pathway promotes APAP- and CCl4-induced injury but protects from ALD, MASLD and ageing-induced injury.
“Together, these data align with the critical role of the β-catenin–WNT pathway in liver injury, promoting APAP- and CCl4-induced injury34 but protecting from ALD36,37, MASLD35,38,39 and ageing-induced injury43.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [35]
RSPO3-LGR4-mediated HSC-hepatocyte communication is a gatekeeper of liver function in health and disease.
“The critical impact of HSC-derived RSPO3 on liver size, zonation, metabolism, regeneration and injury matches findings in mice with hepatocyte-specific deletion of β-catenin or LGR4/524,25,34–39, rendering RSPO3–LGR4-mediated HSC–hepatocyte communication a gatekeeper of liver function in health and disease.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [35]
RSPO3 has seemingly opposing functions in acute toxic liver and chronic metabolic injury, aligning with the functions of its downstream target β-catenin in hepatocyte injury.
“The seemingly opposing functions of RSPO3 in acute toxic liver and chronic metabolic injury align with the functions of its downstream target β-catenin in hepatocyte injury34–39.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [35]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
No references could be resolved yet.
Research works printed but not linked: 29
- Nelson WJ, Nusse R: Convergence of Wnt, beta-catenin, and cad- herin pathways. Science 2004, 303:1483-1487
- Willert K, Nusse R: Beta-catenin: a key mediator of Wnt signaling. Curr Opin Genet Dev 1998, 8:95-102
- Barker N: The canonical Wnt/beta-catenin signalling pathway. Meth- ods Mol Biol 2008, 468:5-15
- Brantjes H, Barker N, van Es J, Clevers H: TCF: lady Justice casting the final verdict on the outcome of Wnt signalling. Biol Chem 2002, 383:255-261
- Hartsock A, Nelson WJ: Adherens and tight junctions: structure, function and connections to the actin cytoskeleton. Biochim Biophys Acta 2008, 1778:660 -669
- Sekine S, Lan BY, Bedolli M, Feng S, Hebrok M: Liver-specific loss of beta-catenin blocks glutamine synthesis pathway activity and cyto- chrome p450 expression in mice. Hepatology 2006, 43:817-825
- Tan X, Behari J, Cieply B, Michalopoulos GK, Monga SP: Conditional deletion of beta-catenin reveals its role in liver growth and regenera- tion. Gastroenterology 2006, 131:1561-1572
- Koteish A, Diehl AM: Animal models of steatosis. Semin Liver Dis 2001, 21:89 -104
- Leclercq IA, Farrell GC, Field J, Bell DR, Gonzalez FJ, Robertson GR: CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. J Clin Invest 2000, 105:1067-1075
- Leclercq IA, Lebrun VA, Starkel P, Horsmans YJ: Intrahepatic insulin resistance in a murine model of steatohepatitis: effect of PPARgamma agonist pioglitazone. Lab Invest 2007, 87:56 -65
- Rinella ME, Green RM: The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance. J Hepatol 2004, 40:47-51
- Apte U, Zeng G, Thompson MD, Muller P, Micsenyi A, Cieply B, Kaestner KH, Monga SP: beta-Catenin is critical for early postnatal liver growth. Am J Physiol Gastrointest Liver Physiol 2007, 292: G1578 -G1585
- Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR: Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 1999, 94:2467-2474
- Folch J, Ascoli I, Lees M, Meath JA, Le BN: Preparation of lipide extracts from brain tissue. J Biol Chem 1951, 191:833-841
- Allain CC, Poon LS, Chan CS, Richmond W, Fu PC: Enzymatic de- termination of total serum cholesterol. Clin Chem 1974, 20:470 -475
- Bucolo G, David H: Quantitative determination of serum triglycerides by the use of enzymes. Clin Chem 1973, 19:476 -482
- Micsenyi A, Tan X, Sneddon T, Luo JH, Michalopoulos GK, Monga SP: Beta-catenin is temporally regulated during normal liver develop- ment. Gastroenterology 2004, 126:1134 -1146
- Rizki G, Arnaboldi L, Gabrielli B, Yan J, Lee GS, Ng RK, Turner SM, Badger TM, Pitas RE, Maher JJ: Mice fed a lipogenic methionine- choline-deficient diet develop hypermetabolism coincident with he- patic suppression of SCD-1. J Lipid Res 2006, 47:2280 -2290
- Maines MD: The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol 1997, 37:517-554
- Tan X, Yuan Y, Zeng G, Apte U, Thompson MD, Cieply B, Stolz DB, Michalopoulos GK, Kaestner KH, Monga SP: Beta-catenin deletion in hepatoblasts disrupts hepatic morphogenesis and survival during mouse development. Hepatology 2008, 47:1667-1679
- Apte U, Singh S, Zeng G, Cieply B, Virji MA, Wu T, Monga SP: Beta-catenin activation promotes liver regeneration after acetamino- phen-induced injury. Am J Pathol 2009, 175:1056 -1065
- Chalasani N, Gorski JC, Asghar MS, Asghar A, Foresman B, Hall SD, Crabb DW: Hepatic cytochrome P450 2E1 activity in nondiabetic pa- tients with nonalcoholic steatohepatitis. Hepatology 2003, 37:544 -550
- Weltman MD, Farrell GC, Hall P, Ingelman-Sundberg M, Liddle C: Hepatic cytochrome P450 2E1 is increased in patients with nonalco- holic steatohepatitis. Hepatology 1998, 27:128 -133
- Weltman MD, Farrell GC, Liddle C: Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflam- mation. Gastroenterology 1996, 111:1645-1653
- Bataller R, Brenner DA: Liver fibrosis. J Clin Invest 2005, 115:209 -218
- Friedman SL: Mechanisms of disease: mechanisms of hepatic fibro- 752 Behari et al AJP February 2010, Vol. 176, No. 2 sis and therapeutic implications. Nat Clin Pract Gastroenterol Hepatol 2004, 1:98 -105
- dela Pena A, Leclercq IA, Williams J, Farrell GC: NADPH oxidase is not an essential mediator of oxidative stress or liver injury in murine MCD diet-induced steatohepatitis. J Hepatol 2007, 46:304 -313
- Ota T, Takamura T, Kurita S, Matsuzawa N, Kita Y, Uno M, Akahori H, Misu H, Sakurai M, Zen Y, Nakanuma Y, Kaneko S: Insulin resistance accelerates a dietary rat model of nonalcoholic steatohepatitis. Gas- troenterology 2007, 132:282-293
- Yamaguchi K, Yang L, McCall S, Huang J, Yu XX, Pandey SK, Bhanot S, Monia BP, Li YX, Diehl AM: Inhibiting triglyceride synthesis im- proves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 2007, 45:1366 -1374
Cited by
Sorted by citations
Angiocrine Wnt signaling controls liver growth and metabolic maturation in mice
Leibing, T., Géraud, C., Augustin, I., Boutros, M., Augustin, H. G., Okun, J. G., Langhans, C., Zierow, J., Wohlfeil, S. A., Olsavszky, V., et al. (2018) · Hepatology · doi:10.1002/hep.29613 · Cited by 116 · see citing works
Hepatic stellate cells control liver zonation, size and functions via R-spondin 3
Sugimoto, A., Saito, Y., Wang, G., Sun, Q., Yin, C., Lee, K. H., Geng, Y., Rajbhandari, P., Hernandez, C., Steffani, M., et al. (2025) · Nature · doi:10.1038/s41586-025-08677-w · Cited by 110 · see citing works
Self-citationYeh, T.-H., Krauland, L., Singh, V., Zou, B., Devaraj, P., Stolz, D. B., Franks, J., Monga, S. P. S., Sasatomi, E., & Behari, J. (2010) · Hepatology · doi:10.1002/hep.23801 · Cited by 81 · see citing works
Self-citationRole and Regulation of Wnt/β-Catenin in Hepatic Perivenous Zonation and Physiological Homeostasis
Goel, C., Monga, S. P., & Nejak-Bowen, K. (2022) · The American Journal of Pathology · doi:10.1016/j.ajpath.2021.09.007 · Cited by 53 · see citing works
Self-citationThe RSPO‐LGR4/5‐ZNRF3/RNF43 module in liver homeostasis, regeneration, and disease
Annunziato, S., Sun, T., & Tchorz, J. S. (2022) · Hepatology · doi:10.1002/hep.32328 · Cited by 45 · see citing works
- Authors
- Behari, J., Yeh, T.-H., Krauland, L., Otruba, W., Cieply, B., Hauth, B., Apte, U., Wu, T., Evans, R., & Monga, S. P. S.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Behari, Jaideep
- Monga, Satdarshan P.S.
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2010-02
- Volume
- 176
- Issue
- 2
- Pages
- 744-753
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC2808081
- OpenAlex
- W1976490723
- Cited by
- 128
- References
- 0
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 9 · 2023: 7 · 2022: 8 · 2021: 10 · 2020: 4 · 2019: 7 · 2018: 7 · 2017: 13 · 2016: 3 · 2015: 8 · 2014: 6 · 2013: 13 · 2012: 6
- FWCI
- 4.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (K08AA017622)
- National Cancer Institute (R01CA124414)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK62277, T32DK063922, DK 063922, R01DK062277)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- β-catenin, Wnt/β-catenin signaling, hepatocyte-specific knockout, steatohepatitis, methionine-choline-deficient diet, hepatic cholesterol homeostasis, bile acid homeostasis, liver fibrosis, hepatic steatosis, liver injury
- MeSH terms
- Animals, Bile Acids and Salts, Cholesterol, Choline Deficiency, Diet, Fatty Liver, Homeostasis, Liver, Liver Cirrhosis, Methionine, Organ Specificity, Stress, Physiological, Mice, Knockout, Genetic Predisposition to Disease, beta Catenin, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
