pAPOE-huPNPLA3-I148M Mouse
Product Name
pAPOE-huPNPLA3-I148M Mouse
Product ID
C002109
Strain Name
C57BL/6Cya-Pnpla3tm2(APOE-hPNPLA3*I148M)/Cya
Background
C57BL/6Cya
Status
When using this mouse strain in a publication, please cite “pAPOE-huPNPLA3-I148M Mouse (Catalog C002109) were purchased from Cyagen.”
Product Type
Age
Genotype
Sex
Quantity
Standard products are sold as live mice derived from cryorecovery or expansion. Frozen materials are available upon request. Pricing and lead times depend on real-time inventory.
Gene Name
PNPLA3
Gene Alias
ADPN, C22orf20, iPLA(2)epsilon
NCBI ID
Chromosome
Chr 22 (Human)
MGI ID
Datasheet
Strain Description
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.
Reference
Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;78(6):1966-1986.
Younossi ZM, Golabi P, de Avila L, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J Hepatol. 2019;71(4):793-801.
Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40(12):1461-1465.
Sookoian S, Pirola CJ. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology. 2011;53(6):1883-1894.
Singal AG, Manjunath H, Yopp AC, et al. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis. Am J Gastroenterol. 2014;109(3):325-334.
Wang Y, Hong S, Hudson H, et al. PNPLA3(148M) is a gain-of-function mutation that promotes hepatic steatosis by inhibiting ATGL-mediated triglyceride hydrolysis. J Hepatol. 2025;82(5):871-881.
BasuRay S, Smagris E, Cohen JC, Hobbs HH. The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Hepatology. 2017;66(4):1111-1124.
Li JZ, Huang Y, Karaman R, et al. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J Clin Invest. 2012;122(11):4130-4144.
Strain Strategy
The sequences from upstream of exon 1 to downstream of exon 8 of the mouse Pnpla3 were replaced with Human APOE promoter-ATG start codon to downstream of exon 9 of human PNPLA3 cassette. The point mutation p.I148M (ATC to ATG) was introduced into the human PNPLA3 exon 3.
Figure 1. Gene editing strategy of pAPOE-huPNPLA3-I148M mice.
Application Area
Mechanistic studies of hepatic metabolic diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction‑associated steatohepatitis (MASH);
Screening, development, and preclinical in vivo evaluation of therapeutic agents targeting PNPLA3-I148M.
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