Yosuke Aihara

Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats

BackgroundDipeptidyl peptidase-4 inhibitor (DPP4-I) is clinically used as a new oral antidiabetic agent. Although DPP4 is reportedly associated with the progression of chronic liver diseases, the effect of DPP4-I on liver fibrosis development is still obscure. This study was designed to elucidate the effect of DPP4-I on liver fibrosis development in conjunction with the activated hepatic stellate cells (Ac-HSCs).MethodsThe antifibrotic effect of DPP4-I was assessed in vivo and in vitro using porcine serum-induced experimental liver fibrosis model. DPP4-I, sitagliptin, at a clinically comparable low dose was administered by gavage daily.ResultsDPP4-I significantly attenuated liver fibrosis development along with the suppression of hepatic transforming growth factor (TGF)-β1, total collagen, and tissue inhibitor of metalloproteinases-1 in a dose-dependent manner. These suppressive effects occurred almost concurrently with the attenuation of HSCs activation. Our in vitro studies showed that DPP4-I inhibited platelet-derived growth factor-BB-mediated proliferation of the Ac-HSCs as well as upregulation of TGF-β1 and α1(I)-procollagen at magnitudes similar to those of the in vivo studies. The inhibitory effects of DPP4-I against HSCs proliferation and fibrogenic gene expression are mediated through the inhibition of the phosphorylation of ERK1/2, p38 and Smad2/3, respectively.ConclusionsDPP4-I markedly inhibits liver fibrosis development in rats via suppression of HSCs proliferation and collagen synthesis. These suppressive effects are associated with dephosphorylation of ERK1/2, p38 and Smad2/3 in the HSCs. Since DPP4-I is widely used in clinical practice, this drug may represent a potential new therapeutic strategy against liver fibrosis in the near future.

Losartan, an angiotensin-II type 1 receptor blocker, attenuates the liver fibrosis development of non-alcoholic steatohepatitis in the rat

BackgroundApart from simple steatosis, the non-alcoholic steatohepatitis (NASH) can progress into liver fibrosis and cirrhosis. To date, however, no widely accepted therapeutic modalities have been established against NASH in the clinical practice. To find out promising new therapeutic agents, it is important to employ an appropriate experimental model of NASH, such as association with insulin resistance.FindingsIn the current study, we found that losartan, a clinically used angiotensin-II type 1 receptor blocker, significantly attenuated a choline-deficient L-amino acid-defined (CDAA) diet-induced steatohepatitis in obese diabetic- and insulin resistance-associated Otsuka Long-Evans Tokushima Fatty (OLETF) rats. The transforming growth factor-beta, a well-known major fibrogenic cytokine, was also suppressed in a similar magnitude to that of the fibrosis area. Noteworthy was the finding that these inhibitory effects were achieved even at a clinically comparable low dose.ConclusionSince losartan is widely used without serious side effects in the clinical practice, this agent may be an effective new therapeutic strategy against NASH.

Combination treatment of angiotensin II type I receptor blocker and new oral iron chelator attenuates progression of nonalcoholic steatohepatitis in rats

Angiotensin II type I receptor blocker and iron chelator reportedly exert suppressive effects on nonalcoholic steatohepatitis (NASH) progression, including liver fibrosis and hepatocarcinogenesis. The aim of this study was to elucidate the combined effect of losartan (LOS), an angiotensin II type I receptor blocker, and deferasirox (DSX), a newly developed oral iron chelator, on the progression of NASH in rats. To induce NASH, F344 rats were fed a choline-deficient l-amino acid-defined diet for 12 wk, and the effects of LOS and DSX at clinically comparable low doses were elucidated in conjunction with oxidative stress, neovascularization, and hepatic stellate cells (HSC) activation, all known to play important roles in the progression of NASH. Treatment with both LOS and DSX suppressed choline-deficient L-amino acid-defined diet-induced liver fibrosis development and hepatocarcinogenesis. This combination treatment exerted a stronger inhibitory effect compared with treatment with a single agent. These inhibitory effects occurred almost concurrently with the suppression of oxidative stress, neovascularization, and HSC activation. Our in vitro study demonstrated that LOS and DSX inhibited angiotensin II-induced proliferation, transforming growth factor-β(1) expression of activated HSC, and in vitro angiogenesis. These results indicated that dual inhibition by combined treatment of LOS and DSX attenuated the progression of NASH. Since both agents are widely used in clinical practice, this combination therapy may represent a potential new strategy against NASH in the near future.

Reduction of endotoxin attenuates liver fibrosis through suppression of hepatic stellate cell activation and remission of intestinal permeability in a rat non-alcoholic steatohepatitis model

Previous clinical studies have demonstrated that endotoxin/toll-like receptor 4 (TLR4) signaling is critical in the inflammatory pathways associated with non-alcoholic steatohepatitis (NASH). In human and animal studies, NASH was associated with portal lipopolysaccharide (LPS) and the plasma LPS level was hypothesized to be associated with small intestinal bacterial overgrowth, change in composition of the microbiota and increased intestinal permeability. The aim of the present study was to investigate the roles of endogenous endotoxin and TLR4 in the pathogenesis of NASH. The effects of antibiotics were assessed in vivo using a choline deficiency amino acid (CDAA)-induced experimental liver fibrosis model. Antibiotics, including polymyxins and neomycins, were orally administered in drinking water. Antibiotics attenuated hepatic stellate cell (HSC) activation and liver fibrosis via TGF-β and collagen in an experimental hepatic fibrosis model. The mechanism by which antibiotics attenuated LPS-TLR4 signaling and liver fibrosis was assessed. Notably, TLR4 mRNA level in the liver was elevated in the CDAA group and the CDAA-induced increase was significantly reduced by antibiotics. However, no significant differences were observed in the intestine among all groups. Elevated mRNA levels of LPS binding protein, which was correlated with serum endotoxin levels, were recognized in the CDAA group and the CDAA-induced increase was significantly reduced by antibiotics. The intestinal permeability of the CDAA group was increased compared with the choline-supplemented amino acid group. The tight junction protein (TJP) in the intestine, determined by immunohistochemical analysis was inversely associated with intestinal permeability. Antibiotics improved the intestinal permeability and enhanced TJP expression. Inhibition of LPS-TLR4 signaling with antibiotics attenuated liver fibrosis development associated with NASH via the inhibition of HSC activation. These results indicated that reduction of LPS and restoration of intestinal TJP may be a novel therapeutic strategy for treatment of liver fibrosis development in NASH.

Combination of branched-chain amino acids and angiotensin-converting enzyme inhibitor suppresses the cumulative recurrence of hepatocellular carcinoma: A randomized control trial

Insulin resistance (IR) is reportedly involved in the progression of hepatocellular carcinoma (HCC). Since neovascularization plays an important role in hepatocarcinogenesis and IR, an angiostatic therapy may be considered as one of the promising approaches for chemoprevention against HCC. The aim of the current study was to examine the combination effect of a clinically used branched-chain amino acid (BCAA) and an angiotensin-converting enzyme inhibitor (ACE-I), both reportedly possess anti-angiogenic and IR-improving activities, on the cumulative recurrence after curative therapy. BCAA granules (Livact; 12 g/day) and/or ACE-I (perindopril; 4 mg/day) were administered after the curative therapy for HCC, and several indices were analyzed. A 48-month follow-up revealed that the combination treatment with BCAA and ACE-I markedly inhibited the cumulative recurrence of HCC under IR conditions, whereas neither single treatment exerted a significant inhibition. The soluble form of the vascular endothelial growth factor (VEGF; a central angiogenic factor) receptor-2 (sVEGFR2) was significantly decreased only three months after the treatment without recurrence. We also observed that IR, determined by the homeostasis model assessment (HOMA-IR), was significantly improved by this regimen, indicating that an inhibitory effect was achieved, at least partly, by coordinated effects of anti-angiogenesis and IR improvement. In conclusion, since both BCAA and ACE-I are widely used in clinical practice with safety, this combination therapy may represent a potential new strategy for chemoprevention against IR-based HCC recurrence in the future. Moreover, sVEGFR2 may become a useful clinical predictive marker of this combination treatment.

Cross talk between toll-like receptor-4 signaling and angiotensin-II in liver fibrosis development in the rat model of non-alcoholic steatohepatitis

The innate immune system, including toll‐like receptor‐4 (TLR4) signaling cascade and angiotensin‐II (AT‐II) play important roles in the progression of liver fibrosis development; the cross talk between TLR4 and AT‐II has not been elucidated yet. The aim of the current study was to elucidate the effect of AT‐II type 1 receptor blocker (ARB), on the liver fibrosis development, especially in conjunction with the interaction of TLR4 and AT‐II in the rat model of non‐alcoholic steatohepatitis.

Direct renin inhibitor, aliskiren, attenuates the progression of non‐alcoholic steatohepatitis in the rat model

Renin is a rate‐limiting enzyme of the renin–angiotensin system (RAS), and several reports have shown that renin plays an important role in several pathological processes. Although RAS is known to play a pivotal role in the progression of non‐alcoholic steatohepatitis (NASH), the role of renin is still obscure. The aim of the current study was to examine the effect of the clinically used direct renin inhibitor (DRI), aliskiren, on the progression of NASH in a rat model.

Development of hepatocellular carcinoma in a patient 13 years after sustained virological response to interferon against chronic hepatitis C: a case report

BackgroundAlthough several recent reports have shown that hepatocellular carcinoma (HCC) developed in patients with chronic hepatitis C (CH-C) even after having a sustained virological response (SVR) to interferon (IFN) therapy, it is not common for HCC to develop more than 10 years after SVR.Case presentationA 73-year-old Japanese man with CH-C who achieved SVR to IFN therapy 13 years ago was admitted into our hospital because of huge multiple liver tumors along with marked elevation of the tumor markers. Several diagnostic modalities strongly suggested HCC, and we performed histopathological examination. After confirming the diagnosis as well-differentiated HCC, we successfully treated these tumors with intensive combination therapies.ConclusionOur report highlights the need for careful follow-up for more than 10 years even if the patients with CH-C achieve SVR to IFN therapy.

Dual blockade of angiotensin-II and aldosterone suppresses the progression of a non-diabetic rat model of steatohepatitis.

Both angiotensin‐II (AT‐II) and aldosterone (Ald) play pivotal roles in the pathogenesis of diseases in several organs including the liver. We previously reported that suppression of AT‐II and Ald with angiotensin‐converting enzyme inhibitor (ACE‐I) and selective Ald blocker (SAB), respectively, attenuated the rat liver fibrogenesis and hepatocarcinogenesis. The aim of our current study was to elucidate the combined effects of ACE‐I and SAB in the progression of a non‐diabetic rat model of steatohepatitis, and the possible mechanisms involved.

Combination of branched-chain amino acid and angiotensin‑converting enzyme inhibitor improves liver fibrosis progression in patients with cirrhosis

An effective therapeutic strategy for suppressing liver fibrosis should improve the overall prognosis of patients with chronic liver diseases. Although enormous efforts are ongoing to develop anti-fibrotic agents, no drugs have yet been approved as anti-fibrotic agents for humans. Insulin resistance (IR) is reportedly involved in the progression of liver fibrosis. The aim of the present study was to evaluate the effect of combination treatment with a clinically used branched-chain amino acid (BCAA) and an angiotensin-converting enzyme inhibitor (ACE-I) on several fibrotic indices in patients with liver cirrhosis under the condition of IR. BCAA granules (Livact; 12 g/day) and/or ACE-I (perindopril; 4 mg/day) were administered, and several indices were analyzed. A 48-month follow-up revealed that the combination treatment with BCAA and ACE-I markedly improved the progression of serum fibrosis markers, whereas single treatment with either BCAA or ACE-I did not exert these inhibitory effects. The plasma level of transforming growth factor-β was significantly attenuated almost in parallel with the suppression of serum fibrosis markers. Furthermore, the combined treatment with BCAA and ACE-I improved the serum albumin level and IR, which was evaluated using the homeostasis model assessment method for IR. Taken together, since both BCAA and ACE-I are widely used with safety in clinical practice, these results indicate that this combination therapy may represent a potential new future strategy against liver fibrosis development in patients with liver cirrhosis under the condition of IR.