The hedgehog pathway in nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of obesity-associated liver diseases and it has become the major cause of cirrhosis in the Western world. The high prevalence of NAFLD-associated advanced liver disease reflects both the high prevalence of obesity-related fatty liver (hepatic steatosis) and the lack of specific treatments to prevent hepatic steatosis from progressing to more serious forms of liver damage, including nonalcoholic steatohepatitis (NASH), cirrhosis, and primary liver cancer. The pathogenesis of NAFLD is complex, and not fully understood. However, compelling evidence demonstrates that dysregulation of the hedgehog (Hh) pathway is involved in both the pathogenesis of hepatic steatosis and the progression from hepatic steatosis to more serious forms of liver damage. Inhibiting Hedgehog signaling enhances hepatic steatosis, a condition which seldom results in liver-related morbidity or mortality. In contrast, excessive Hedgehog pathway activation promotes development of NASH, cirrhosis, and primary liver cancer, the major causes of liver-related deaths. Thus, suppressing excessive Hh pathway activity is a potential approach to prevent progressive liver damage in NAFLD. Various pharmacologic agents that inhibit Hh signaling are available and approved for cancer therapeutics; more are being developed to optimize the benefits and minimize the risks of inhibiting this pathway. In this review we will describe the Hh pathway, summarize the evidence for its role in NAFLD evolution, and discuss the potential role for Hh pathway inhibitors as therapies to prevent NASH, cirrhosis and liver cancer.

Pathogenesis of NASH: the Impact of Multiple Pathways

“…The Hedgehog pathway consists of a complex signaling cascade that is important for the immune response and is essential in embryogenesis but can be activated later in life in the setting of tissue regeneration [102]. In mice, Hedgehog pathway activation resulted from liver fat injury and was associated with steatohepatitis and fibrosis [103].…”

Cyclopamine and Rapamycin Synergistically Inhibit mTOR Signalling in Mouse Hepatocytes, Revealing an Interaction of Hedgehog and mTor Signalling in the Liver

“…By using mice in which hepatocyte-specific Hh has been deleted and in vitro experiments, we demonstrate a strong mutual interaction between Hh signalling and the mTOR pathway in healthy mouse hepatocytes. This study reveals new insights on the high complexity of the signalling network that controls liver energy metabolism and contributes to our comprehension of diseases caused by the dysregulation of these two pathways like non-alcoholic fatty liver disease or macrocephaly-associated conditions [15][16][17]. Therapies often target only one signalling pathway; however, targeting several parts of the regulating network may be a substantially more effective approach.…”

The Association between SOCS1−1656G>A Polymorphism, Insulin Resistance and Obesity in Nonalcoholic Fatty Liver Disease (NAFLD) Patients

“…In the current obesity epidemic, NAFLD is among the most common causes of chronic liver disease [1]. This condition encompasses a spectrum of obesity-associated liver diseases, including nonalcoholic steatohepatitis (NASH), cirrhosis, and primary liver cancer [2]. The true prevalence of NAFLD and NASH is unknown, and several efforts have been made to identify patients with increased risk of progression to advanced fibrosis [3,4].…”

“…Dysregulated expression and/or secretion of transcription factors and cytokines, respectively, influence downstream metabolic pathways and play a crucial role in NAFLD pathogenesis. In obese individuals with NAFLD, the enhanced production of inflammatory cytokines—such as IL-6 and TNF-α—by adipose tissue macrophages may contribute to the development of insulin resistance [2]. Recently, emphasis has been placed on genetic factors that may have a role in NAFLD etiology [6], and some genetic polymorphisms involved in the development of the disease (e.g., PNPLA3, TM6SF2, APOB) were identified by a genome-wide association study (GWAS) [7].…”