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Heterocyclic Amines Disrupt Lipid Homeostasis in Cryopreserved Human Hepatocytes
Kennedy M Walls1,2, Jonathan Y Joh1, Kyung U Hong1,3
1Department of Pharmacology and Toxicology and Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
Cardiovascular Toxicology
|June 8, 2024
Summary
Heterocyclic amines (HCAs) from cooked meat can cause fat accumulation in liver cells. This study shows HCAs disrupt lipid metabolism, potentially contributing to metabolic dysfunction-associated steatohepatitis (MASH).
Area of Science:
- Hepatology and metabolic disease research.
- Environmental toxicology and its impact on liver health.
- Molecular mechanisms of steatosis and insulin resistance.
Background:
- Metabolic dysfunction-associated steatohepatitis (MASH) is linked to metabolic syndrome and environmental factors.
- Heterocyclic amines (HCAs), formed during meat cooking, are implicated in insulin resistance.
- Previous research linked HCAs to insulin resistance but not hepatic lipid homeostasis.
Purpose of the Study:
- To investigate the effects of common HCAs (MeIQx and PhIP) on lipid homeostasis in human hepatocytes.
- To determine if HCAs contribute to fat accumulation and dysregulated lipid metabolism in the liver.
- To explore the molecular pathways affected by HCA exposure in hepatocytes.
Main Methods:
- Utilized cryopreserved human hepatocytes for in vitro exposure studies.
- Administered MeIQx and PhIP at a concentration of 25 μM.
- Analyzed changes in lipid droplets, triglycerides, gene expression (PNPLA3, HSD17B13, PLIN2, FASN, DGAT2, CPT1A, SCD, CD36, PON1), and intracellular cholesterol.
Main Results:
- Exposure to MeIQx or PhIP significantly increased lipid droplets and triglycerides in hepatocytes.
- Both HCAs upregulated genes involved in lipid synthesis, transport, and metabolism (e.g., FASN, DGAT2, CD36).
- HCA exposure increased intracellular cholesterol and decreased PON1 expression, impacting cholesterol efflux.
Conclusions:
- HCAs significantly dysregulate lipid production, metabolism, and storage in human hepatocytes.
- HCA exposure leads to fat accumulation, a key feature of MASH.
- This study provides the first evidence that HCAs may contribute to the development of MASH.
