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Receptor Biology and Signal Transduction

MON-263 - 7Α-Hydroxy-4-Cholesten-3-One (C4) Identifies MASLD Patients with Glucose Intolerance and Increased Waist Circumference.

Monday, June 15, 2026
9:00 AM - 2:00 PM CT
Location: ENDOExpo; Poster Floor
Disclosure(s):
Lucilla Crudele, MD, PhD: No financial relationships to disclose
Antonio MOSCHETTA: No financial relationships to disclose


Background: The gut-liver axis is fundamental in the regulation of both lipid and glucose metabolism. In normal conditions, 95% of Bile Acids (BA) that arrive in the gut are reabsorbed and travel back to the liver, 5% travel through the colon to be excreted into faeces. Besides their key role in lipid absorption in the gut, BA are ligands of the nuclear Farnesoid X receptor (FXR) with subsequent induction of the enterokine FGF19, that inhibits hepatic BA synthesis but also decreases hepatic lipogenesis, increases fatty acid-oxidation, regulates glucose metabolism and promotes insulin sensitivity. Thus, we focused on BA and investigated their role in the pathogenesis of Metabolic-dysfunction Associated Steatotic Liver Disease (MASLD).

Methods: Clinical history was recorded, and physical examination, anthropometric measures, biochemical assessment, and abdomen ultrasound were performed to detect MASLD in 301 (156M,145F) subjects. BAs measurements on serum and faeces were collected using untargeted and targeted mass spectrometry methods. Also C4 (7α-hydroxy-4-cholesten-3-one), a marker of BA synthesis from cholesterol, was measured. Non-invasive scores of atherosclerosis (AIP), liver steatosis (HSI, FLI) and adiposopathy (VAI) were computed.

Results: MASLD was present in 70% of our sample. Total serum BA did not differ between MASLD and no-MASLD subjects, nor did the hydrophobicity index and primary-to-secondary BA ratio. In contrast, MASLD patients showed significantly higher total faecal BA (p < 0.05). Serum C4 was significantly higher in MASLD subjects compared to no-MASLD (p < 0.001). Moreover, in MASLD patients, C4 levels positively correlated with fasting glucose (r=0.17, p< 0.05), HbA1c (r=0.14, p< 0.05), triglycerides (r=0.27, p< 0.0001), BMI (r=0.17, p< 0.05), waist circumference (r=0.22, p< 0.01), AIP (r=0.30, p< 0.0001), HSI (r=0.25, p< 0.001), FLI (r=0.22, p< 0.005), and VAI (r=0.31, p< 0.0001), while no significant correlations were observed in no-MASLD individuals. Finally, we found significantly higher C4 levels in patients with worse fasting glucose (p < 0.05) and HbA1c (p < 0.005) levels.

Conclusions: Despite similar circulating BA levels, MASLD is characterized by increased faecal BA excretion with subsequent enhanced hepatic liver BA synthesis, as reflected by elevated serum C4. The strong associations between C4 and metabolic, steatosis, and adiposity-related indices, exclusively observed in MASLD patients, indicate that dysregulated BA synthesis is closely linked to metabolic dysfunction and dysbiosis. These findings support a pivotal role of the FXR–FGF19 axis in the pathophysiology of MASLD and identify C4 as a clinically relevant biomarker of altered BA homeostasis in metabolic diseases. Moreover, our results provide a clinical rationale for investigating therapeutic strategies targeting the FXR–FGF19 axis in MASLD.

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