Our results revealed that (1) lifestyle intervention can trigger genome-wide differential DNA methylation changes in human NAFLD; (2) both LCD and ELCD intervention on human NAFLD can induce same DNA methylation alterations at critical genes in blood, e.g., GAB2, which was also validated in liver and adipose of NASH mice after LFD and ELFD intervention; (3) methylation of CpG units (i.e., CpG_10.11.12) inversely correlated with mRNA expression GAB2 in adipose tissue of NASH mice after ELFD intervention. The gene discussed is GAB2; the disease is metabolic dysfunction-associated steatotic liver disease.