Cytokeratin-18 increase as a signal for early liver cell changes in high-fat diet-induced obesity before overt steatohepatitis.

OBJECTIVE

The major cause of non-alcoholic fatty liver disease (NAFLD) is obesity; in fact, this condition has been defined as metabolic dysfunction-associated steatotic liver disease (MASLD). Non-invasive diagnosis and grading of NAFLD are the subjects of the studies. Cytokeratin-18 (CK-18) is particularly highlighted as an indicator of liver cell death and steatohepatitis, but its relationship with obesity remains unclear. This study aimed to evaluate the metabolic parameters, CK-18 levels, and liver histopathology in high-fat diet-induced obesity in rats.

METHODS

Rats were fed either a normal-fat diet (NFD) or a high-fat diet (HFD) for eight weeks. Body weights, metabolic-liver parameters and CK-18 levels were assessed at study end. The liver histopathological changes (steatosis, lobular inflammation, ballooning, fibrosis) and NAFLD activity score were examined.

RESULTS

Increased final body weight (335.8 ± 20.2 vs 291.5 ± 6.25 g; p<0.001), glucose (186.4 ± 46.9 vs 130.0 ± 16.2 mg/dL; p=0.011), insulin (4.30 ± 0.70 vs 2.23 ± 0.82 IU/L; p<0.001), HOMA-IR (2.03 ± 0.79 vs 0.73 ± 0.34; p=0.003), ALT (72.34 ± 12.35 vs 55.43 ± 5.75 U/L; p=0.009) and CK-18 (1.46 ± 0.18 vs 0.88 ± 0.18 ng/mL; p<0.001) levels and decreased AST/ALT ratio (1.16 ± 0.09 vs 1.32 ± 0.14; p=0.020) were observed in HFD group compared to NFD group. Histologically, all HFD specimens showed ballooning (8/8) and half showed steatosis (4/8). NAFLD score remained ≤3 in all specimens nevertheless CK-18 values tended to co-occur with higher ALT levels and ballooning formation within the HFD group.

CONCLUSION

HFD-induced obesity was associated with increased CK-18 and the hepatocellular changes as remarkable ballooning without the overt steatohepatitis. These findings support CK-18 interpreting as a signal for early hepatocellular injury in obesity.