Objective: Dysregulated hepatic de novo lipogenesis has been shown to contribute to the pathogenesis of Non-Alcoholic Fatty Liver Diseases in both humans and rodents. Transcription factor Carbohydrate responsive elementbinding protein ( ChREBP) is one of the key regulators of de novo lipogenesis in hepatic cells. Therefore, ChREBP appears as a potential therapeutic target and an accurate knowledge of the mechanisms involved in regulating its expression and activation is crucial for the development of pharmacological approaches for the treatment of metabolic diseases Methods: The molecular control of ChREBP nuclear localization is complex. We use in vitro cell culture and in vivo animal models to understand the Results: This study for the first time shows that expression of hepatic calcium channel blocker (CA) a cytosolic partner of ChREBP is negatively associated with the de novo lipogenesis. Here using in vitro and in vivo approaches we demonstrated that chronic sucrose diet or exposure to high fat diet results in downregulation of CA and subsequent transcriptional activation of ChREBP and hepatic de novo lipogenesis. Moreover, Hepatocyte cells lacking CA exhibit ChREBP’s exclusive nuclear localization and enhanced lipid droplets accumulation. Interestingly, reintroduction CA into sucrose and high fat diet exposed mice largely restricts ChREBP to the cytosol and ameliorate liver steatosis, hepatotoxicity, confers protection against sucrose and high fat induced fat accumulation and improves glucose tolerance. Conclusion: Thus, overexpressing CA could serve as an adaptive strategy to improve physiological homeostasis during obesity, and its associated metabolic disorder.