Leptin Promotes the Myofibroblastic Phenotype in Hepatic Stellate Cells by Activating the Hedgehog Pathway

Abstract

Trans-differentiation of quiescent hepatic stellate cells (Q-HSCsLeptin-ObRb interactions were not necessary for HSC transdifferentiation to occur in vitro or in vivo but are important because liver fibrogenesis was attenuated in db/db mice. These findings reveal that leptin activates Hh signaling to alter gene expression programs that control cell fate and have important implications for liver fibrosis and other leptin-regulated processes involving EMTs, including development, obesity, and cancer metastasis.

HOTAIR Epigenetically Modulates PTEN Expression via MicroRNA-29b: A Novel Mechanism in Regulation of Liver Fibrosis

“…The primers of Col1A1, a-SMA, and GAPDH were designed as described previously. 25,43 To detect miR-29a, miR-29b, and miR-29c expressions, reverse transcription reactions were performed using the TaqMan MicroRNA Assay (Applied Biosystems) according to the manufacturer's instructions. The GAPDH (Applied Biosystems) level was used to normalize the relative abundance of HOTAIR and mRNAs.…”

Smoothened is a master regulator of adult liver repair

“…Finally, the model has potential relevance for regeneration of other epithelial tissues with resident stellate cell/pericyte populations, such as adult pancreas and kidney (64). Our studies suggested that conditional deletion of SMO in αSMA-expressing cells reduced num-cells per mm 2 in DMEM supplemented with 10% fetal bovine serum and penicillin/streptomycin, as described previously (11).…”

“…Adenoviruses, harboring either the GFP gene (AdGFP) or Cre recombinase gene (AdCre), were added to primary murine HSCs at culture day 4 at a MOI of 50, as described previously (11). After 24 hours, virus-containing medium was aspirated and replaced with fresh medium.…”

“…Hh signaling is tightly regulated in adulthood. Healthy livers barely express Hh ligands, and neither mature hepatocytes nor cholangiocytes exhibit active Hh signaling (11)(12)(13). Both types of mature liver epithelial cells begin to produce Hh ligands, however, when subjected to lethal stresses or certain injury-associated cytokines (7,14).…”

The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis

“…Other factors implicated in HSCs activation include the Hedgehog (Hh) pathway, 110 cytokine stimulation (particularly TNF-a, IL-1b, and IL-6), 111 and leptin. 112 Conversely, adiponectin released from adipose tissue reduces HSC migration and proliferation. 113 Finally, TLR4 contributes to the activation of HSCs through the MyD88-NF-kB-dependent pathway.…”