Steatohepatitis: A tale of two “hits”?

Day, Christopher P.; James, Oliver

doi:10.1016/s0016-5085(98)70599-2

Cited by 3,795 publications

(2,919 citation statements)

References 24 publications

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“…The two‐hit theory proposed by Day has been widely supported as explaining the mechanism of NASH onset and progression (Day & James, 1998; Day, 2002). Initially, a fatty liver is induced as “the first hit” by hepatic fat accumulation arising from lifestyle diseases.…”

Section: Introductionmentioning

confidence: 99%

Porphyromonas gingivalis induced periodontitis exacerbates progression of non‐alcoholic steatohepatitis in rats

Kuraji

Fujita

et al. 2016

Clinical & Exp Dental Res

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Non‐alcoholic steatohepatitis (NASH) is a chronic liver disease that can develop into hepatocirrhosis and hepatic carcinoma. In recent years, epidemiological and animal studies have reported that Porphyromonas gingivalis (P. gingivalis), a known periodontopathic bacteria, is closely related to NASH. However, previous studies could not demonstrate a direct relationship between periodontitis, P. gingivalis infection, and NASH. The purpose of the present study was to examine the impact of P. gingivalis‐associated periodontitis on the onset and progression of NASH. Forty‐two male Wistar rats were used in this study. Rats were fed a high‐fat diet (HFD) for 12 weeks in order to induce fatty liver. At 4 weeks from the start of feeding, the animals were performed ligature placement around the maxillary first molar tooth in order to induce experimental periodontitis, and then a P. gingivalis slurry was applied around the ligature twice in a week for 8 weeks (HFD/Pg(+) group). Controls were given the slurry without P. gingivalis after ligature placement using the same protocol (HFD/Pg(−) group). Significant increases in alveolar bone resorption and inflammation in periodontal tissue around the molar tooth in the HFD/Pg(+) group were observed when compared with the HFD/Pg(−) group. Moreover, histological images showing NASH characterized by perivenular lipid deposition including big fatty drops, ballooning degeneration, and focal necrosis with inflammatory cells were confirmed in the liver of rats in the HFD/Pg(+) group. Significant increases in alanine aminotransaminase, aspartate aminotransferase, and C‐reactive protein levels were observed in the HFD/Pg(+) group. Furthermore, endotoxin levels in serum in the HFD/Pg(+) group were significantly higher than those in the HFD/Pg(−) group. The present study demonstrated that experimental periodontitis induced by P. gingivalis led to the progression of NASH in rats with fatty liver. Increased levels of endotoxin derived from P. gingivalis infection appear to play a considerable role in the progression of NASH.

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Section: Introductionmentioning

confidence: 99%

Porphyromonas gingivalis induced periodontitis exacerbates progression of non‐alcoholic steatohepatitis in rats

Kuraji

Fujita

et al. 2016

Clinical & Exp Dental Res

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“…The ''two-hit'' hypothesis involves a sequential process where first steatosis develops and a second hit is caused by oxidative stress resulting in lipid peroxidation and steatohepatitis [5]. A second theory involves ''multiple parallel hits'' [6].…”

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confidence: 99%

Hepatic fibrosis developing in morbid obesity independent of steatohepatitis: new mechanism or the Rube Goldberg machine?

Kallwitz

2012

Hepatol Int

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“…In summary, the present results demonstrate that a single administration of a specific S. mutans strain at 4 weeks triggers the initiation of NASH as the second hit in the ‘two-hit theory’ [14], causing NASH-like features at 16 weeks and leading to fibrosis by 20 weeks, which became severe by 48 weeks. In contrast, an HFD alone only caused NASH-like findings after 48 weeks.…”

Section: Discussionmentioning

confidence: 82%

“…The ‘two-hit theory’ is widely accepted as the mechanism of NASH development, in which insulin-resistance due to metabolic syndrome caused by excess nutrition leads to simple steatosis as the first step. Oxidative stress, lipid peroxidation, and functional failure of mitochondria accelerate inflammation and fibrosis in the liver as the second step, causing NASH [14]. …”

Section: Introductionmentioning

confidence: 99%

Longitudinal comparison of Streptococcus mutans-induced aggravation of non-alcoholic steatohepatitis in mice

Naka

Wato

Hatakeyama

et al. 2018

Journal of Oral Microbiology

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Background: We previously reported that intravenous administration of Streptococcus mutans strain TW871 caused typical non-alcoholic steatohepatitis (NASH)-like findings in a high-fat diet (HFD) mouse model at 16 weeks after initiating the experiment. Objective: The purpose of the present study was to analyse mice administered S. mutans TW871 fed a HFD for various periods of time. Methods: First, 6-week-old C57BL/6J mice were fed an HFD for 4 weeks, then TW871 (1 × 107 CFU) or phosphate-buffered saline (PBS) were intravenously administered. Mice were euthanized 12, 16, 20, and 48 weeks after starting the experiment, and conventional clinical and histopathological evaluations were performed. Results: Typical NASH-like findings were not identified in the mice at 12 weeks, while they were observed in the TW871 group at 16 weeks, and the severity of NASH symptoms were increased at 20 weeks. Furthermore, signs of severe NASH were also observed at 48 weeks. In contrast, in the PBS-administered group, the NASH findings were identified only at 48 weeks and no typical NASH features were observed at 12, 16, or 20 weeks. Conclusion: These results suggest that intravenous administration of a specific S. mutans strain aggravates NASH in a time-dependent manner in the mice in contrast to mice without S. mutans exposure.

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Steatohepatitis: A tale of two “hits”?

Cited by 3,795 publications

References 24 publications

Porphyromonas gingivalis induced periodontitis exacerbates progression of non‐alcoholic steatohepatitis in rats

Porphyromonas gingivalis induced periodontitis exacerbates progression of non‐alcoholic steatohepatitis in rats

Hepatic fibrosis developing in morbid obesity independent of steatohepatitis: new mechanism or the Rube Goldberg machine?

Longitudinal comparison of Streptococcus mutans-induced aggravation of non-alcoholic steatohepatitis in mice

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