Significance and Mechanism of CYP7a1 Gene Regulation during the Acute Phase of Liver Regeneration

Abstract

Cholesterol 7alpha-hydroxylase (CYP7a1) is the rate-limiting enzyme in the classic pathway of bile acid synthesis. Expression of CYP7a1 is regulated by a negative feedback pathway of bile acid signaling. Previous studies have suggested that bile acid signaling is also required for normal liver regeneration, and CYP7a1 expression is strongly repressed after 70% partial hepatectomy (PH). Both the effect of CYP7a1 suppression on liver regrowth and the mechanism by which 70% PH suppresses CYP7a1 expression are unknown. Here we show that liver-specific overexpression of an exogenous CYP7a1 gene impaired liver regeneration after 70% PH, which was accompanied by increased hepatocyte apoptosis and liver injury. CYP7a1 expression was initially suppressed after 70% PH in an farnesoid X receptor/ small heterodimer partner-independent manner; however, both farnesoid X receptor and small heterodimer partner were required to regulate CYP7a1 expression at the later stage of liver regeneration. c-Jun N-terminus kinase and hepatocyte growth factor signaling pathways are activated during the acute phase of liver regeneration. We determined that hepatocyte growth factor and c-Jun N-terminus kinase pathways were involved in the suppressing of the CYP7a1 expression in the acute phase of live regeneration. Taken together, our results provide the significance that CYP7a1 suppression is required for liver protection after 70% PH and there are two distinct phases of CYP7a1 gene regulation during liver regeneration.

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

“…Cyp7a1 levels must rapidly decrease post PH, otherwise bile acids accumulate and cause hepatocyte apoptosis. 48 Paralleling DPB, Cyp7a1 mRNA levels were higher in HET livers pre-and post PH (Supplementary Figure 6), confirming higher levels of a functional DBP protein in HET livers. DBP also influences lipid metabolism by inducing insulin-like growth factor binding protein 1 (IGFBP1), which downregulates INSIG2, an inhibitor of de novo lipogenesis.…”

The role of bile salts in liver regeneration

“…While diet containing 0.2 % cholic acid is stimulatory, feeding of a 1.0 % cholic acid diet resulted in mortality in hepatectomized mice indicating that toxic bile salt levels had been reached [40]. PHx in mice is accompanied by decreased basolateral uptake and synthesis of bile salts, while bile salt secretion is increased [41].…”

“…PHx in mice is accompanied by decreased basolateral uptake and synthesis of bile salts, while bile salt secretion is increased [41]. Fxr-dependent downregulation of Cyp7a1 accounts for decreased bile salt synthesis in mice after PHx [40]. When Cyp7a1 is not suppressed due to genetic Fxr deficiency or transgenic overexpression of CYP7A1, liver regeneration is impaired by outbalanced apoptosis and decreased DNA synthesis resulting in reduced post-PHx survival [40].…”

“…Fxr-dependent downregulation of Cyp7a1 accounts for decreased bile salt synthesis in mice after PHx [40]. When Cyp7a1 is not suppressed due to genetic Fxr deficiency or transgenic overexpression of CYP7A1, liver regeneration is impaired by outbalanced apoptosis and decreased DNA synthesis resulting in reduced post-PHx survival [40]. Above notions stress the importance of strict maintenance of intrahepatic bile salt homeostasis for proper progression of liver regeneration.…”

FXR and liver carcinogenesis

“…Huang et al found that FXR-dependent BA signaling was required for [9] . In response to the increased BA flux after 70% PH, FXR activates hepatic SHP and intestinal FGF15, which results in the suppression of Cyp7A1 and BA synthesis [9,61,62] . Another FXR target gene, the bile salt export pump (BSEP), a canalicular BA effluxer [63] , can also be induced to enhance BA export [9] .…”