Understanding NASH and MASH
The terminology for fatty liver disease has evolved to better reflect its metabolic etiology:
Current Nomenclature
MAFLD
Metabolic Associated Fatty Liver Disease
Broader term encompassing hepatic steatosis associated with metabolic dysfunction, regardless of alcohol consumption.
MASLD
Metabolic Dysfunction Associated Steatotic Liver Disease
Current preferred terminology for non alcoholic fatty liver disease.
MASH
Metabolic Dysfunction Associated Steatohepatitis
The progressive form with inflammation and hepatocyte injury, previously termed NASH (non alcoholic steatohepatitis).
Disease Progression
Simple Steatosis
Hepatic fat accumulation (>5% of hepatocytes) without significant inflammation. Often reversible with lifestyle intervention.
Steatohepatitis (MASH)
Steatosis plus lobular inflammation, hepatocyte ballooning, and injury. Risk of progression to fibrosis.
Fibrosis
Collagen deposition and architectural distortion. Staged F0 to F4.
Cirrhosis
Advanced fibrosis with nodule formation. Risk of hepatocellular carcinoma and liver failure.
Dietary Models
High Fat Diet Models
Standard High Fat Diet (HFD)
45% to 60% fat calories produces obesity and hepatic steatosis in C57BL/6 mice over 12 to 24 weeks. Produces mild steatohepatitis but minimal fibrosis.
Western Diet
High fat plus high fructose/sucrose mimics Western dietary patterns. More severe metabolic phenotype than HFD alone.
Fast Food Diet
High fat, high cholesterol, high fructose combination produces more severe disease with fibrosis.
Specialized Dietary Models
Choline Deficient High Fat Diet (CDHFD)
Choline deficiency accelerates steatohepatitis and fibrosis development. Widely used for rapid disease induction.
Methionine Choline Deficient Diet (MCD)
Produces severe steatohepatitis and fibrosis but with weight loss rather than obesity. Does not model metabolic syndrome.
AMLN Diet (Amylin Liver NASH)
High trans fat, high fructose, high cholesterol diet produces obesity, steatohepatitis, and fibrosis with metabolic syndrome features.
DIAMOND Model
Isogenic C57BL/6J 129S1/SvImJ hybrid on Western diet develops full disease spectrum including hepatocellular carcinoma.
Genetic Models
Lipid Metabolism Genes
PNPLA3 I148M Knockin
The most common genetic risk variant for fatty liver disease in humans. Knockin mice with the human I148M variant develop more severe steatosis and fibrosis on lipogenic diets.
TM6SF2 E167K Knockin
Second most common variant. Affects VLDL secretion and hepatic lipid accumulation.
HSD17B13 Loss of Function
Protective variant in humans. HSD17B13 knockout mice show altered lipid metabolism.
MBOAT7 Variants
Membrane bound O acyltransferase 7 variants affect phospholipid remodeling.
Insulin Signaling and Metabolism
Liver Specific Insulin Receptor Knockout (LIRKO)
Hepatocyte insulin resistance model. Develops steatosis and glucose intolerance.
PTEN Liver Knockout
Severe steatohepatitis and hepatocellular carcinoma development.
FXR Knockout
Farnesoid X receptor deficiency affects bile acid and lipid metabolism.
Inflammatory Pathway Models
NLRP3 Inflammasome
Inflammasome activation drives steatohepatitis. NLRP3 knockout or knockin models for pathway analysis.
ASK1 Pathway
Apoptosis signal regulating kinase 1 mediates lipotoxic injury.
TLR4 and Innate Immunity
Toll like receptor signaling contributes to inflammation and fibrosis.
Model Design Considerations
Background Strain Selection
Metabolic phenotypes are profoundly strain dependent:
C57BL/6
Susceptible to diet induced obesity and steatosis. Standard background for MASH studies.
C57BL/6J vs C57BL/6N
Substrains differ in metabolic phenotypes. C57BL/6J carries Nnt mutation affecting glucose metabolism.
129 Strains
Generally resistant to diet induced obesity but susceptible when combined with genetic modifications.
BALB/c
Different metabolic response than C57BL/6.
Cell Type Specific Approaches
MASH involves multiple liver cell types:
| Cell Type | Cre Driver | Application |
|---|---|---|
| Hepatocyte Specific | Albumin Cre | Targets hepatocytes for studying cell autonomous lipid metabolism and injury responses. |
| Kupffer Cell/Macrophage | LysM Cre or CX3CR1 Cre | Targets resident and infiltrating macrophages for inflammation studies. |
| Hepatic Stellate Cell | LRAT Cre | Targets stellate cells for fibrosis mechanism studies. |
| Cholangiocyte | CK19 Cre or Sox9 Cre | Targets bile duct contributions. |
Phenotyping MASH Models
Metabolic Assessment
- Body Composition:Weight, fat mass, lean mass by DEXA or MRI.
- Glucose Homeostasis:IPGTT, ITT, fasting glucose and insulin, HOMA IR.
- Lipid Profiles:Plasma triglycerides, cholesterol, free fatty acids.
Liver Assessment
- Liver Weight and Triglycerides:Hepatomegaly and hepatic lipid content.
- Histopathology:H&E for steatosis, inflammation, and ballooning. NAFLD Activity Score (NAS) for standardized grading.
- Fibrosis Staging:Sirius red or trichrome staining. Alpha SMA immunohistochemistry. Hydroxyproline content.
Therapeutic Applications
MASH models support preclinical development of multiple therapeutic approaches:
Combination Approaches
Advanced MASH may require combination therapy targeting multiple disease mechanisms. Patient variant knockins, cell type specific deletions, and reporter integration enable sophisticated preclinical studies of complex therapeutic strategies.
Selected Publications in MASH Research
According to PubMed, recent publications demonstrate the utility of genetically engineered mouse models in MASH research:
Zhou Y et al. (2025).
FAM83A acts as an amplifier for lipogenic signaling to facilitate the pathogenesis of metabolic dysfunction associated steatohepatitis. ↗Metabolism 166: 156164
Xu D et al. (2025).
Decreased LONP1 expression exacerbates MASH induced liver fibrosis via elevated orotic acid levels. ↗Journal of Hepatology Online ahead of print
What Researchers Say
“I've been working with iTL over the past 5 years in the production of 3 different genetically altered mice. Not only did iTL help in the design of the mice, but the entire process was transparent with the opportunity at any time along the way to discuss my questions or concerns with scientists who had significant insight into the process. The mice were delivered on time, as billed!”
— Raghu Mirmira, MD, PhD
University of Chicago
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