Hepatocyte-Specific Casein Kinase 1 Epsilon Ablation Ameliorates Metabolic Dysfunction–Associated Steatohepatitis by Up-Regulating Tumor Necrosis Factor Receptor–Associated Factor 3 in Mice

Abstract

Casein kinase 1 epsilon (CK1ε), a member of the serine/threonine protein kinase family, is known to phosphorylate a broad range of substrates. However, its role in the development of chronic liver diseases remains elusive. This study aimed to investigate the role of CK1ε in the development and progression of metabolic dysfunction-associated steatohepatitis (MASH). Hepatocyte-specific CK1ε knockout (CK1εΔHEP) mice were generated by crossbreeding mice with floxed CK1ε alleles (CK1εfl/fl) and Cre-expressing albumin mice. Mice were fed either a Western diet (WD) or a methionine- and choline-deficient diet to induce MASH. CK1εΔHEP was associated with a decreased severity of WD- or methionine- and choline-deficient diet-induced MASH, as confirmed by reduced incidence of hepatic lesions and significantly lower levels of alanine aminotransferase, aspartate aminotransferase, and proinflammatory cytokine tumor necrosis factor (TNF)-α. CK1εΔHEP WD-fed mice exhibited significant amelioration of total cholesterol, triglycerides, and de novo lipogenic genes, indicating that CK1ε could influence lipid metabolism. CK1εΔHEP WD-fed mice showed significantly down-regulated TNF receptor-associated factor 3, phosphorylated (p) transforming growth factor-β-activated kinase 1, p-TANK-binding kinase 1, and p-AKT levels, thereby affecting downstream mitogen-activated protein kinase signaling, indicating a potential mechanism for the observed rescue. Finally, pharmacologic inhibition of CK1ε with PF670462 improved palmitic acid-induced steatohepatitis invitro and attenuated WD-induced metabolic profile invivo. In conclusion, CK1ε up-regulates TNF receptor-associated factor 3, which, in turn, causes transforming growth factor-β-activated kinase 1-dependent signaling, amplifies downstream mitogen-activated protein kinase signaling, modifies p-c-Jun levels, and exacerbates inflammation, all of which are factors in WD-induced metabolic dysfunction-associated steatotic liver disease.