mTOR Signaling Reshapes Bile Acid Profiles and Drives Metabolic Liver Disease
New research links mTORC1-TFEB/TFE3 signaling to bile acid remodeling, revealing how nutrient sensing shapes fatty liver disease risk.
Summary
The liver's nutrient sensor mTORC1 is linked not only to fat metabolism but also to bile acid composition. This primarily mouse-based study associated altered mTORC1–TFEB/TFE3 signaling with changes in bile acid synthesis and transformation. Depending on the signaling state, changes in Cyp2c70 and Cyp8b1 expression and cholesterol trafficking accompanied shifts toward either non–12-hydroxylated or 12-hydroxylated bile acids. Tfe3 deletion or rapamycin attenuated or reversed these effects. Liver-specific Lamtor2 deletion also disrupted liver architecture and metabolism. Protein restriction, which inhibits mTORC1, reshaped bile acids in mice and correlated with improved metabolic outcomes in people with metabolic dysfunction-associated steatotic liver disease (MASLD). The findings link nutrient signaling to bile acid metabolism but do not establish that protein restriction or mTORC1 inhibition improves human liver disease.
Detailed Summary
mTORC1 integrates nutrient and hormonal signals to regulate liver metabolism. Bile acids are synthesized from cholesterol and enable intestinal lipid absorption; their composition is also associated with metabolic health. The introduction notes that 12-hydroxylated (12-OH) bile acids are enriched in metabolic dysfunction-associated steatotic liver disease (MASLD) and advanced steatohepatitis (MASH). This study investigated whether altered mTORC1 signaling, including its regulation of TFEB and TFE3, is associated with changes in liver cell identity, lipid metabolism and bile acid composition.
The supplied results describe chronic liver-specific Lamtor2 deletion using Alb-Cre and acute deletion in adult hepatocytes using AAV8-TBG-Cre. Lamtor2 belongs to the Ragulator complex, which helps target mTORC1 to the lysosome. Chronic deletion distorted liver architecture, producing small periportal hepatocytes and mitochondrial abnormalities. Liver glycogen and serum glucose were lower, while body and liver weight were unaffected. Bile duct hyperplasia occurred in 4 of 5 animals at approximately 1.5 years of age. Acute adult deletion caused progressive weight loss, increased liver weight and notable liver injury. Its carbohydrate-storage phenotype differed from that of the chronic model; clear cytoplasm was not interpreted as evidence of steatosis on morphology alone.
Single-nucleus RNA sequencing of 23,590 liver nuclei across four genotypes identified 10 cell populations, including four hepatocyte subpopulations. Approximately 35% of sequenced nuclei in chronic Lamtor2-knockout livers expressed biliary or liver progenitor-like markers, including Pkhd1, Spp1, Prom1 and Sox9. These findings indicate substantial transcriptional heterogeneity and altered cell-state signatures following Lamtor2 deletion.
The abstract reports that changes in Cyp2c70 and Cyp8b1 expression, together with altered cholesterol trafficking, were associated with shifts toward non–12-OH or 12-OH bile acid species depending on the mTORC1 signaling state. Tfe3 deletion or rapamycin treatment attenuated or reversed these effects. Protein restriction, which inhibits mTORC1, also reshaped bile acid profiles in mice and correlated with improved metabolic outcomes in MASLD patients.
Overall, the study supports context-dependent links between nutrient signaling and bile acid remodeling. The genetic models caused substantial liver abnormalities, and the human findings are correlational. The supplied text does not establish that dietary protein restriction or pharmacological mTORC1 inhibition improves human liver disease.
Key Findings
- Single-nucleus RNA-seq of 23,590 liver nuclei identified 10 cell populations, including four hepatocyte subtypes, across four genotypes
- About 35% of nuclei in chronic Lamtor2-knockout livers expressed biliary/progenitor markers (Pkhd1, Spp1, Prom1, Sox9)
- Bile duct hyperplasia appeared in 80% (4 of 5) of approximately 1.5-year-old chronic Lamtor2-knockout mice
- Acute adult hepatocyte Lamtor2 deletion caused progressive weight loss, increased liver weight and notable liver injury
- Depending on mTORC1 signaling state, Cyp2c70/Cyp8b1 expression changes and altered cholesterol trafficking were associated with shifts toward non–12-OH or 12-OH bile acids
- Tfe3 deletion or rapamycin treatment attenuated or reversed the bile acid remodeling effects reported in the abstract
- Protein restriction, which inhibits mTORC1, reshaped bile acid profiles in mice and correlated with improved metabolic outcomes in MASLD patients
Methodology
The supplied results describe chronic Alb-Cre-mediated liver-specific Lamtor2 deletion and acute adult hepatocyte deletion using AAV8-TBG-Cre, alongside tdTomato lineage tracing. Readouts included histology, ultrastructural analysis, metabolic measurements, gene and protein expression, and single-nucleus RNA sequencing of 23,590 nuclei across four genotypes. Figure 1 reports n = 5 to 7 for several chronic-model measurements, n = 3 to 6 for several acute-model measurements, and n = 2 mice per genotype for the isolated-cell protein analysis; it specifies two-tailed unpaired Student’s t tests. The abstract additionally reports Tfe3 deletion, rapamycin treatment, protein restriction, bile acid remodeling and correlations with metabolic outcomes in MASLD patients, but the supplied text does not provide their detailed protocols or statistical analyses.
Study Limitations
The Lamtor2-deletion models caused liver injury or architectural abnormalities and may not represent physiological or dietary modulation of mTORC1. Several reported mouse measurements used small cohorts; the late-life bile duct hyperplasia observation involved only five animals. The bile acid conclusions are framed as context-dependent associations, and the human MASLD findings are correlational rather than evidence of treatment efficacy. The supplied source ends partway through the results, limiting verification of detailed bile acid experiments and human analyses; no conflict-of-interest disclosure is included.
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