NASH-related increases in plasma bile acid levels depend on insulin resistance

• Published in: JHEP reports Vol. 3; no. 2; p. 100222
• Main Authors: Grzych, Guillaume, Chávez-Talavera, Oscar, Descat, Amandine, Thuillier, Dorothée, Verrijken, An, Kouach, Mostafa, Legry, Vanessa, Verkindt, Hélène, Raverdy, Violeta, Legendre, Benjamin, Caiazzo, Robert, Van Gaal, Luc, Goossens, Jean-Francois, Paumelle, Réjane, Francque, Sven, Pattou, François, Haas, Joel T., Tailleux, Anne, Staels, Bart
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2021; Elsevier
• Subjects: Bile acids; Diabetes; Insulin resistance; Life Sciences; NAFLD; NASH; Obesity; Translational study; FXR; NAFLD; TUDCA; UDCA; GCDCA; C4; GDCA; ABOS; HbA1c; NAFL; CA; GHCA; CDCA; Obesity; GLCA; Bile acids; DCA; GCA; GUDCA; HCA; T2D; IR; TDCA; GHDCA; LCA; NASH; HOMA2; TCDCA; THDCA; Translational study; MAFLD; TLCA; TCA; THCA; Insulin resistance; Diabetes; HDCA; FPG; OGTT; ADA; BA; GHDCA, glycohyodeoxycholic acid; THDCA, taurohyodeoxycholic acid; DCA, deoxycholic acid; T2D, type 2 diabetes; GLCA, glycolithocholic acid; NAFLD, non-alcoholic fatty liver disease; GUDCA, glycoursodeoxycholic acid; TCDCA, taurochenodeoxycholic acid; FPG, fasting plasma glycaemia; GCDCA, glycochenodeoxycholic acid; HCA, hyocholic acid; HOMA2, homeostatic model assessment 2; C4, 7alpha-hydroxy-4-cholesten-3-one; GHCA, glycohyocholic acid; CA, cholic acid; OGTT, oral glucose tolerance test; GCA, glycocholic acid; UDCA, ursodeoxycholic acid; BA, bile acids; HDCA, hyodeoxycholic acid; LCA, lithocholic acid; FXR, farnesoid-X-receptor; THCA, taurohyocholic acid; GDCA, glycodeoxycholic acid; NAFL, non-alcoholic fatty liver; NASH, non-alcoholic steatohepatitis; TDCA, taurodeoxycholic acid; CDCA, chenodeoxycholic acid; ABOS, Biological Atlas of Severe Obesity; ADA, American Diabetes Association; MAFLD, metabolic associated fatty liver disease; TUDCA, tauroursodeoxycholic acid; HbA1c, glycated haemoglobin; TLCA, taurolithocholic acid; TCA, taurocholic acid; IR, insulin resistance
• ISSN: 2589-5559; 2589-5559
• DOI: 10.1016/j.jhepr.2020.100222

Plasma bile acids (BAs) have been extensively studied as pathophysiological actors in non-alcoholic steatohepatitis (NASH). However, results from clinical studies are often complicated by the association of NASH with type 2 diabetes (T2D), obesity, and insulin resistance (IR). Here, we sought to dissect the relationship between NASH, T2D, and plasma BA levels in a large patient cohort. Four groups of patients from the Biological Atlas of Severe Obesity (ABOS) cohort (Clinical Trials number NCT01129297) were included based on the presence or absence of histologically evaluated NASH with or without coincident T2D. Patients were matched for BMI, homeostatic model assessment 2 (HOMA2)-assessed IR, glycated haemoglobin, age, and gender. To study the effect of IR and BMI on the association of plasma BA and NASH, patients from the HEPADIP study were included. In both cohorts, fasting plasma BA concentrations were measured. Plasma BA concentrations were higher in NASH compared with No-NASH patients both in T2D and NoT2D patients from the ABOS cohort. As we previously reported that plasma BA levels were unaltered in NASH patients of the HEPADIP cohort, we assessed the impact of BMI and IR on the association of NASH and BA on the combined BA datasets. Our results revealed that NASH-associated increases in plasma total cholic acid (CA) concentrations depend on the degree of HOMA2-assessed systemic IR, but not on β-cell function nor on BMI. Plasma BA concentrations are elevated only in those NASH patients exhibiting pronounced IR. Non-alcoholic steatohepatitis (NASH) is a progressive liver disease that frequently occurs in patients with obesity and type 2 diabetes. Reliable markers for the diagnosis of NASH are needed. Plasma bile acids have been proposed as NASH biomarkers. Herein, we found that plasma bile acids are only elevated in patients with NASH when significant insulin resistance is present, limiting their utility as NASH markers. [Display omitted] •Bile acids have been studied as pathophysiological actors and biomarkers in NASH.•Plasma BAs have been reported to be higher in NASH vs. No-NASH patients.•Plasma BAs are altered in patients with T2D, IR, and obesity, risk factors for NASH.•Thus, the independent association between plasma BA increases and NASH is unclear.•NASH-associated increases in plasma BA depend on the degree of insulin sensitivity.