Hepatocyte Mitogen‐Activated Protein Kinase Kinase 7 Contributes to Restoration of the Liver Parenchyma Following Injury in Mice

Abstract

MAP kinase kinase (MKK) 7 and MKK4 are upstream activators of c-Jun NH 2-terminal kinases (JNKs) and have been shown to be required for the early development of the liver. Although it has been suggested that MKK7 might be involved in the regulation of hepatocyte proliferation, the functional role of MKK7 in the liver has remained unclear. Here, we examined phenotypic alterations in liver-or hepatocyte/hematopoietic cell-specific MKK7 knockout (KO) mice, which were generated by crossing MKK7 LoxP/LoxP with Alb-Cre or Mx1-Cre mice, respectively. The livers of Alb-Cre-/+ MKK7 LoxP/LoxP mice developed without discernible tissue disorganization. MKK7 KO mice responded normally to liver injuries incurred by partial hepatectomy or injection of CCl 4. However, tissue repair following CCl 4-induced injury was delayed in MKK7 KO mice compared with that of control mice. Furthermore, after repeated injections of CCl 4 for 8 weeks, the liver in MKK7 KO mice showed intense fibrosis with increased protractive hepatocyte proliferation, suggesting that MKK7 deficiency might affect regenerative responses of hepatocytes in the altered tissue microenvironment. MKK7 KO hepatocytes demonstrated normal proliferative activity when cultured in monolayers. However, MKK7 KO significantly suppressed branching morphogenesis of hepatocyte aggregates within a collagen gel matrix. Microarray analyses revealed that suppression of branching morphogenesis in MKK7 KO hepatocytes was associated with a reduction in mRNA expression of Tagln, Glipr2, and Plau, and forced expression of these genes in MKK7 KO hepatocytes partially recovered the attenuated morphogenesis. Furthermore, hepatocyte-specific overexpression of Plau rescued the impaired tissue repair of MKK7 KO mice following CCl 4-induced injury. Conclusion: MKK7 is dispensable for the regenerative proliferation of hepatocytes but plays important roles in repair processes following parenchymal destruction, possibly through modulation of hepatocyteextracellular matrix interactions.

Nicotine exposure of male mice protects offspring against carbon tetrachloride‐induced acute liver injury

“…[ 25 ] Some studies have shown that tissue repair and cellular regeneration have a critical role in differential sensitivity to CCl 4 hepatotoxicity. [ 26,27 ]…”

“…[25] Some studies have shown that tissue repair and cellular regeneration have a critical role in differential sensitivity to CCl 4 hepatotoxicity. [26,27] The Wnt signaling pathway plays an important role in a variety of biological processes. It is essential for the growth and development of the liver.…”

Aberrant differentiation and proliferation of hepatocytes in chronic liver injury and liver tumors

“…60 We examined the effects of hepatocyte-specific knockout of MKK7 on the regenerative proliferation of hepatocytes following partial hepatectomy or acute CCl 4 injury and found that the loss of MKK7 does not affect hepatocyte proliferation, suggesting that the JNK-c-Jun signaling pathway is dispensable for hepatocyte proliferation itself. 61 However, since the loss of MKK7 delays the tissue repair process following CCl 4 injury, the JNK-c-Jun pathway is likely involved in the tissue repair process through the modulation of hepatocyte-extracellular matrix interactions. 61 Myc suppression through siRNA-mediated RNA interference inhibits DNA synthesis in mouse hepatocytes in primary culture.…”

MKK4 Inhibitors—Recent Development Status and Therapeutic Potential

“…MKK7 and JNK1 are to be considered anti-targets. Since their activity is responsible for liver regeneration [119,122], these must not be targeted by the inhibitors. In recent years, the development of selective MKK4 inhibitors serving liver therapy purposes has risen [119,[123][124][125].…”