The natural polyphenol compound resveratrol improved liver inflammation and fibrosis associated with nonalcoholic steatohepatitis (NASH) in mouse models, according to Japanese researchers.
However, use of resveratrol didn't inhibit steatosis as represented in a high-fat diet-induced model of nonalcoholic fatty liver disease (NAFLD) in the studies, published in Scientific Reports.
The study was led by Takaomi Kessoku, MD, of Yokohama City University Graduate School of Medicine.
NASH is believed to lead to liver cirrhosis and/or liver cancer. Currently, efforts to manage NASH focus on lifestyle changes, but -- as Kessoku and his colleagues pointed out -- preventing the progression of fibrosis and inflammation solely through something like weight loss via calorie restriction is very difficult. "Therefore, development of effective pharmacotherapy is required," they wrote.
Resveratrol is naturally found in foods such as grapes, peanuts, cocoa, some berries, and red wine. Some research has suggested that resveratrol may provide a wide range of health-related benefits, although confirmation in controlled studies has been elusive.
In the context of NASH, resveratrol's anti-inflammatory and anti-oxidant characteristics could help protect the human nervous and cardiac systems, and also work as an anti-tumor agent, Kessoku and his colleagues noted. But the "exact effect of resveratrol on steatosis ... or fibrosis and inflammation (major phenotypes of nonalcoholic steatosis [NASH]) is not known," they wrote.
Also, previous studies have produced contradictory conclusions about the effect of resveratrol on NAFLD and NASH. "Thus, the effect of resveratrol on steatosis is controversial," they wrote.
Consequently, Kessoku and his colleagues investigated whether the administration of resveratrol improves steatosis -- as well as inflammation and fibrosis -- in NAFLD and NASH.
The researchers divided mice into four groups -- one with a basal diet, another receiving a high-fat diet, a third receiving a high-fat diet mixed with resveratrol at 2 mg/kg/day (HFD-resveratrol2), and the fourth received an HFD mixed with resveratrol at 20 mg/kg/day (HFD-resveratrol20).
The mice were fed the basal or high-fat for 12 weeks, and resveratrol was administered either during the last 2 weeks, or the last 4 weeks. Mice on high fat had elevated hepatic triglyceride and ALT levels, and had steatosis confirmed by Oil Red O staining.
Kessoku and his colleagues found that the administration of resveratrol -- after both 2 and 4 weeks -- did not significantly reduce hepatic triglyceride or alanine transaminase levels, or suppress the development of steatosis.
They did find however, that the administration of resveratrol significantly inhibited mRNA levels of hepatic CD14. The researchers pointed out that since CD14 expression is a marker of activation of Kupffer cells in the liver -- believed to cause liver inflammation and fibrosis -- they needed to look at the effect resveratrol had on ameliorating those conditions.
Kessoku and his colleagues then analyzed the effect the administration of resveratrol would have on a low-dose lipopolysaccharide (LPS)-induced model of NASH. LPS is to believed contribute to liver damage in both alcoholic steatohepatitis and NASH.
The researchers repeated their four-group study, this time also administering a single, low dose of LPS (0.25 mg/kg/day).
The researchers conducted a histological evaluation of the liver in these groups using NAFLD activity scores (NAS) and fibrosis staging. They found that the increased NAS and fibrosis stage seen in HFD-fed LPS-administered mice was substantially reduced in those mice treated with resveratrol.
Specifically, Kessoku and his colleagues found that lobular inflammation and hepatocyte ballooning in NAS decreased considerably, and that hepatic fibrosis was "suppressed dramatically," as demonstrated through SR and Masson Trichrome staining (and confirmed by expression of the mRNA for fibrosis markers).
"In summary, we showed that, in a mouse model of NASH/NAFLD, resveratrol administration can improve inflammation and fibrosis, but not steatosis, via inhibition of LPS reactivity that is due to CD14 expression in Kupffer cells," Kessoku and his colleagues concluded. "Our results suggest that resveratrol could be a candidate agent for the NASH treatment."
Authors reported no potential conflicts of interest.
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