The I148M PNPLA3 Variant Forces Progressive Portal MASLD by Spatially Perturbing Metabolic Pathways Across Liver...

Area of Science:

• Hepatology and Molecular Biology
• Genetics of Liver Disease
• Spatial Transcriptomics

Background:

• Genetic factors, particularly the I148M variant in Patatin-like phospholipase domain containing 3 (PNPLA3), significantly influence metabolic dysfunction-associated steatotic liver disease (MASLD) progression.
• Hepatic zonation, the spatial organization of hepatocytes, plays a role in liver metabolism and may be affected by genetic modifiers like the PNPLA3 variant.

Purpose of the Study:

• To investigate the impact of the I148M PNPLA3 variant on metabolic processes across different liver zones (portal and central) using spatial transcriptomics.
• To understand how this genetic variant influences the distribution of steatosis, inflammation, and fibrosis within the liver lobule.

Main Methods:

• Spatial transcriptomics (Visium CytAssist) was employed on liver biopsies from MASLD patients with wild-type or homozygous I148M PNPLA3 variants (Discovery cohort, n=4).
• Hepatocytes from portal (PZ) and central (CZ) zones were spatially mapped and analyzed for metabolic activity.
• A validation cohort (n=100) assessed the distribution of steatosis, inflammation, and fibrosis based on PNPLA3 genotype.

Main Results:

• I148M PNPLA3 variant carriers showed altered metabolic profiles in PZ hepatocytes, with higher lipid turnover and glucose signaling, and lower mitochondrial activity compared to CZ hepatocytes.
• The I148M variant was associated with increased PNPLA3 expression and non-parenchymal cell enrichment in the PZ, correlating with more severe injury.
• Validation cohort confirmed a pronounced PZ distribution of steatosis, inflammation, and fibrosis in I148M PNPLA3 subjects versus wild-type.

Conclusions:

• The I148M PNPLA3 variant disrupts normal hepatic zonation, promoting steatosis in the PZ and leading to mitochondrial dysfunction.
• This genetic variant induces metabolic switching across liver zones and defines a specific histological pattern in MASLD.
• Spatial transcriptomics reveals the localized impact of genetic variants on liver disease pathogenesis, offering new clinical perspectives.