pAPOE-huPNPLA3-I148M Mouse

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, characterized by excessive hepatic fat accumulation. Driven by metabolic risk factors, such as obesity, type 2 diabetes, and insulin resistance, MASLD can progressively advance to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and ultimately hepatocellular carcinoma (HCC) ^[1-2]. PNPLA3-I148M (rs738409 C>G) is currently recognized as the strongest genetic susceptibility factor for MASLD. Individuals carrying this variant exhibit significantly increased hepatic fat content, with an approximately 2- to 3.5-fold increase in the risk of developing MASH, fibrosis, and cirrhosis, and this effect may act independently or synergistically with metabolic factors including obesity and insulin resistance ^[3-5]. Mechanistically, the PNPLA3-I148M mutant protein inhibits ATGL-mediated triglyceride (TG) hydrolysis by sequestering ABHD5, leading to hepatic lipid accumulation. Concurrently, this mutation triggers lipidomic remodeling characterized by enrichment of unsaturated fatty acids, elevated ceramides, and depletion of n-3 polyunsaturated fatty acids, and activates oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and inflammatory signaling pathways (e.g., STAT3), ultimately promoting hepatic stellate cell activation and fibrosis progression ^[6-7]. Studies have shown that the use of the human APOE promoter can drive specific high-level expression of PNPLA3-I148M in the liver, thereby recapitulating the human fatty liver phenotype associated with this variant in animal models ^[8].

The pAPOE-huPNPLA3-I148M mice are a disease model generated via gene editing, in which the murine Pnpla3 locus is replaced by a human PNPLA3 sequence driven by the human APOE promoter, with a p.I148M mutation (ATC to ATG) introduced into exon 3. This model is suitable for investigating the mechanisms of hepatic metabolic disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), as well as for drug screening, development, and preclinical in vivo evaluation targeting PNPLA3-I148M.