Modulation of membrane type 1-matrix metalloproteinase by 3,5,4'-trihydroxybibenzyl, an aromatic dihydrostilbene, against perpetual pancreatic stellate cell activation in pancreatogenic diabetes

Upon pancreatic injury or inflammatory events, extracellular matrices (ECMs), such as type-I collagen and fibronectin, are massively produced by activated pancreatic stellate cells (PSCs) for tissue repair and/or regeneration. In chronic pancreatitis, the aberrant PSC activation promotes pathologic ECM stiffness of pancreatic parenchyma, and results in fibrogenesis, permanent tissue destruction and systemic complications.

According to recent statistics, over 50% of chronic pancreatitis patients develop diabetes as the disease progresses. Substantial decrease of beta-cell area was observed in these patients, so as overt hyperglycemia and abated insulin secretion. Such endocrine deficiency secondary to pancreatitis is now classified as pancreatogenic diabetes or type 3c diabetes mellitus (T3cDM), a subtype that has been consistently underestimated. In line with the clinical reports, our preliminary trials demonstrated that chronic pancreatitis mice exhibited impaired glucose tolerance in addition to PSC activation and pathological fibrosis. Their mass of endocrine beta cells and transcript levels of beta-cell genes, namely insulin, Pdx-1, MafA and FoxM1, were conjointly diminished. As 80% of T3cDM cases are ascribed to chronic pancreatitis, we postulate that the molecular signals and matrices from activated PSCs in the fibrotic inflammatory milieu are detrimental to beta-cell biology.

Over the past decades, trans-resveratrol has been scrutinized for numerous health- promoting benefits; however, it has a poor systemic bioavailability. In this regard, we synthesized 3,5,4′-trihydroxybibenzyl (THB) via resveratrol structural modification. Upon eliminating the central aliphatic double bond, the structural flexibility and solubility of THB are largely enhanced. As THB exists as a resveratrol metabolite without further breakdown in the human bowel, it possesses a precious bioavailability. Our preliminary results showed that THB suppressed PSC phenotype in vitro and ameliorated fibrotic conditions in chronic pancreatitis mice in a manner superior to trans-resveratrol. Despite modest structural difference, the mitigation of THB, but not trans-resveratrol, on PSC phenotype and pancreatic fibrosis involved a down-regulation of membrane type 1-matrix metalloproteinase (MT1-MMP), an interstitial peptidase that cleaves ECMs and transduces signals instigating perpetual PSC activation via autocrine loops. In co- culturing assays, THB reduced beta-cell apoptosis while preserving beta-cell functions against PSCs or inflammatory cytokines.

Therefore, we hypothesize that THB preserves beta-cell mass and functions in pancreatogenic diabetes via attenuating PSC phenotype and MT1-MMP-mediated fibrogenesis. In this proposal, we aim to explore the deactivation of PSCs by THB and RNAi of MT1-MMP in cellular experiments; and elucidate the involvement of MT1- MMP in pancreatogenic diabetes utilizing a transgenic mouse model complemented with chronic pancreatitis.