Metabolically Dysfunctional-Associated Steatotic Liver Disease (MASLD) affects both metabolically healthy obese (MHO) individuals and metabolically unhealthy lean (MUL) individuals. Key genes linked to liver dysfunction, such as MLXIPL, PPARA, and FGF21, are under-researched in humans. We aimed to evaluate the ChREBP–PPARα–FGF21 axis in relation to metabolic liver dysfunction in MHO and MUL individuals. Liver histopathology, biochemical data, anthropometric measurements, mRNA expression as analyzed by qPCR, and heatmap visualization were utilized to identify relationships among variables and discern gene expression patterns. ChREBP–PPARA–FGF21 genes were analyzed in liver, subcutaneous (SAT), and omental adipose tissue (OAT) biopsies from 55 subjects, including metabolically unhealthy obese (MUO), MHO, MUL, and metabolically healthy lean (MHL) subjects as controls. The MHL, MUL, MHO, and MUO groups showed a gradual increase in liver PPARα, with a downward trend in ChREBPβ levels in SAT (p < 0.05). Liver ChREBPβ positively correlated with insulin resistance and FGF21. Levels of OAT ChREBPβ showed a negative correlation with anthropometric measurements and serum insulin levels. These findings suggest coordinated regulation under metabolic stress. Increased FGF21 expression in the MUL and MUO groups may aid as a metabolic biomarker of impaired energy homeostasis and compensatory hepatic response.