Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation

Area of Science:

• Hepatology
• Gastroenterology
• Metabolic Diseases

Background:

• Nonalcoholic fatty liver disease (NAFLD) affects 25% of adults.
• A subset of NAFLD patients are lean, with poorly understood pathophysiology.
• Investigating lean NAFLD is crucial for understanding disease heterogeneity.

Purpose of the Study:

• To explore the roles of bile acids (BAs) and gut microbiome in lean NAFLD pathogenesis.
• To compare metabolic and genetic factors between lean and nonlean NAFLD patients.
• To identify potential therapeutic targets for lean NAFLD.

Main Methods:

• Analyzed serum BAs, fibroblast growth factor (FGF) 19, and genetic variants (PNPLA3, TM6SF2) in 538 NAFLD patients and 30 lean controls.
• Characterized gut microbiota profiles in patients and murine models.
• Utilized a murine model treated with an apical sodium-dependent BA transporter inhibitor (SC-435).

Main Results:

• Lean NAFLD patients exhibited more favorable metabolic and histological profiles.
• Higher secondary BA and FGF19 levels, with reduced C4, were observed in lean NAFLD, particularly in early fibrosis stages.
• Distinct gut microbiota profiles were identified in lean NAFLD patients and murine models.
• SC-435 treatment improved steatohepatitis in lean mice, altering BA and microbiota profiles.

Conclusions:

• Metabolic adaptations differentiate lean from nonlean NAFLD.
• Bile acid and gut microbiome alterations are key in lean NAFLD pathophysiology.
• These findings suggest novel therapeutic strategies for lean NAFLD.