Gene expression最新文献

The Hippo pathway and its effector protein YAP (a transcriptional coactivator) have been identified as important in the biology of both hepatocellular carcinoma and cholangiocarcinoma. First identified as a tumor suppressor pathway in Drosophila, the understanding of the mammalian YAP signaling and its regulation continues to expand. In its "on" function, the canonical regulatory Hippo pathway, a well-described serine/threonine kinase module, regulates YAP function by restricting its subcellular localization to the cytoplasm. In contrast, when the Hippo pathway is "off," YAP translocates to the nucleus and drives cotranscriptional activity. Given the role of Hippo/YAP signaling in hepatic malignancies, investigators have sought to target these molecules; however, standard approaches have not been successful based on the pathways' negative regulatory role. More recently, additional regulatory mechanisms, such as tyrosine phosphorylation, of YAP have been described. These represent positive regulatory events that may be targetable. Additionally, several groups have identified potentiating feed-forward signaling for YAP in multiple contexts, suggesting other experimental therapeutic approaches to interrupt these signaling loops. Herein we explore the current data supporting alternative YAP regulatory pathways, review the described feed-forward signaling cascades that are YAP dependent, and explore targeting strategies that have been employed in preclinical models of hepatic malignancies.

Nonalcoholic steatohepatitis (NASH) is the second leading cause of liver transplantation in the US with a high risk of liver-related morbidities and mortality. Given the global burden of NASH, development of appropriate therapeutic strategies is an important clinical need. Where applicable, lifestyle modification remains the primary recommendation for the treatment of NASH, even though such changes are difficult to sustain and even insufficient to cure NASH. Bariatric surgery resolves NASH in such patients where lifestyle modifications have failed, and is recommended for morbidly obese patients with NASH. Thus, pharmacotherapies are of high value for NASH treatment. Though no drug has been approved by the US Food and Drug Administration for treatment of NASH, substantial progress in pharmacological development has been made in the last few years. Agents such as vitamin E and pioglitazone are recommended in patients with NASH, and yet concerns about their side effects remain. Many agents targeting various vital molecules and pathways, including those impacting metabolic perturbations, inflammatory cascades, and oxidative stress, are in clinical trials for the treatment of NASH. Some agents have shown promising results in phase II or III clinical trials, but more studies are required to assess their long-term effects. Herein, we review the potential strategies and challenges in therapeutic approaches to treating NASH.

Sterol 12α-hydroxylase (CYP8B1) is required for the synthesis of cholic acid in the classic bile acid synthesis pathway and plays a role in dyslipidemia and insulin resistance. However, the mechanism of the involvement of Cyp8b1 in dyslipidemia and insulin resistance is not known. CYP8B1 mRNA and protein expression are elevated in diabetic and obese (db/db) mouse liver. In this study adenovirus-mediated transduction of CYP8B1 was used to study the effect of Cyp8b1 on lipid metabolism in mice. Results show that Ad-Cyp8b1 increased 12α-hydroxylated bile acids and induced sterol regulatory element-binding protein 1c (Srebp-1c)-mediated lipogenic gene expression. Interestingly, Ad-Cyp8b1 increased ceramide synthesis and activated hepatic mechanistic target of rapamycin complex 1 (mTORC1)-p70S6K signaling cascade and inhibited AKT/insulin signaling in mice. Ad-Cyp8b1 increased free fatty acid uptake into mouse primary hepatocytes. Ceramides stimulated S6K phosphorylation in both mouse and human primary hepatocytes. In high-fat diet-fed mice, Ad-Cyp8b1 reduced fibroblast growth factor 21 (FGF21), activated intestinal farnesoid X receptor (FXR) target gene expression, increased serum ceramides, VLDL secretion, and LDL cholesterol. In high-fat diet-induced obese (DIO) mice, Cyp8b1 ablation by adenovirus-mediated shRNA improved oral glucose tolerance, increased FGF21, and reduced liver triglycerides, inflammatory cytokine expression, nuclear localization of Srebp-1c and phosphorylation of S6K. In conclusion, this study unveiled a novel mechanism linking CYP8B1 to ceramide synthesis and mTORC1 signaling in dyslipidemia and insulin resistance, via intestinal FXR-mediated induction of FGF15 and liver FGF21. Reducing cholic acid synthesis may be a potential therapeutic strategy to treat dyslipidemia and nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a common liver disease and a major cause of related complications such as cirrhosis and hepatocellular carcinoma (HCC). NAFLD progresses through the stages of simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and HCC. However, NAFLD usually cannot be diagnosed in a timely manner, which is largely attributed to the asymptomatic features of NAFLD patients and the lack of an effective and accurate noninvasive screening approach. Although liver biopsy has been recognized as a gold standard for diagnosing NAFLD, this approach is not suitable for screening and monitoring NAFLD because of its high cost and invasiveness. Several noninvasive screening and diagnostic systemic assessments have been developed in recent years for NAFLD evaluation. Here we summarize the current status and methods for NAFLD diagnosis, including both noninvasive (imaging, biomarkers) and invasive (liver biopsy) assessments. We further discuss the advantages and disadvantages of these developed diagnostic approaches for NAFLD.

Studies using genetic mouse models that have defective autophagy have led to the conclusion that macroautophagy/autophagy serves as a tumor suppressor. One of such models is the liver-specific Atg5 or Atg7 knockout mice, and these knockout mice develop spontaneous liver tumors. It has been generally agreed that p62-mediated Nrf2 activation plays a critical role in promoting autophagy deficiency-induced liver injury and liver tumorigenesis. The mechanisms of how persistent Nrf2 activation induces liver injury and tumorigenesis are incompletely known. We discuss the recent progress on the new roles of HMGB1 and Yap in regulating liver injury and tumorigenesis in mice with liver-specific autophagy deficiency.

Cholestasis results in blockage of bile flow whether the point of obstruction occurs extrahepatically or intrahepatically. Bile acids are a primary constituent of bile, and thus one of the primary outcomes is acute retention of bile acids in hepatocytes. Bile acids are normally secreted into the biliary tracts and then released into the small bowel before recirculating back to the liver. Retention of bile acids has long been hypothesized to be a primary cause of the associated liver injury that occurs during acute or chronic cholestasis. Despite this, a surge of papers in the last decade have reported a primary role for inflammation in the pathophysiology of cholestatic liver injury. Furthermore, it has increasingly been recognized that both the constituency of individual bile acids that make up the greater pool, as well as their conjugation status, is intimately involved in their toxicity, and this varies between species. Finally, the role of bile acids in drug-induced cholestatic liver injury remains an area of increasing interest. The purpose of this review is to critically evaluate current proposed mechanisms of cholestatic liver injury, with a focus on the evolving role of bile acids in cell death and inflammation.

The term blood-bile barrier (BBlB) refers to the physical structure within a hepatic lobule that compartmentalizes and hence segregates sinusoidal blood from canalicular bile. Thus, this barrier provides physiological protection in the liver, shielding the hepatocytes from bile toxicity and restricting the mixing of blood and bile. BBlB is primarily composed of tight junctions; however, adherens junction, desmosomes, gap junctions, and hepatocyte bile transporters also contribute to the barrier function of the BBlB. Recent findings also suggest that disruption of BBlB is associated with major hepatic diseases characterized by cholestasis and aberrations in BBlB thus may be a hallmark of many chronic liver diseases. Several molecular signaling pathways have now been shown to play a role in regulating the structure and function and eventually contribute to regulation of the BBlB function within the liver. In this review, we will discuss the structure and function of the BBlB, summarize the methods to assess the integrity and function of BBlB, discuss the role of BBlB in liver pathophysiology, and finally, discuss the mechanisms of BBlB regulation. Collectively, this review will demonstrate the significance of the BBlB in both liver homeostasis and hepatic dysfunction.