TABLE 1.

Histology of livers from Nrf2^+/+ and Nrf2^−/− mice fed a high-fat diet for 24 weeks

Parameter	Valuef (n)
	RC diet	HF diet
NASa (maximum 8)
Nrf2+/+ mice	0.5 (10)	3.45 (11)
Nrf2−/− mice	2.0 (9)	4.9 (10)
Steatosis component of NASb (0–3)
Nrf2+/+ mice	0.9 (10)	2.55 (11)
Nrf2−/− mice	1.33 (9)	2.4 (10)
Inflammatory component of NASc (0–3)
Nrf2+/+ mice	0 (10)	0.82 (11)
Nrf2−/− mice	0.66 (9)	2.3 (10)
Ballooning component of NASd (0–2)
Nrf2+/+ mice	0 (10)	0 (11)
Nrf2−/− mice	0 (9)	0.3 (10)
Fibrosis stagee (0–3)
Nrf2+/+ mice	0 (10)	0 (11)
Nrf2−/− mice	0 (9)	1 (10)

^aIn Nrf2^+/+ mice, the NAS is significantly higher in livers of HF-fed mice than in RC-fed animals (Kruskal-Wallis H test; P = 0.002), and the same is seen in livers of HF-fed Nrf2^−/− mice compared to RC-fed Nrf2^−/− livers. The HF-fed Nrf2^−/− mice had a significantly higher NAS than HF-fed Nrf2^+/+ mice (Kruskal-Wallis H test; P = 0.03).

^bBoth HF-fed Nrf2^+/+ and Nrf2^−/− mice had more steatosis than their RC-fed counterparts (Kruskal-Wallis H test; P = 0.03). No significant difference was observed between Nrf2^+/+ and Nrf2^−/− mice fed the same diet.

^cThe inflammatory component of the NAS was significantly higher in livers of HF-fed Nrf2^−/− mice than in either HF-fed Nrf2^+/+ or RC-fed Nrf2^−/− mice (Kruskal-Wallis H test; P = 0.002).

^dNo statistical differences were observed for ballooning between the experimental groups.

^eThe median values are shown, and fibrosis was observed only in livers of HF-fed Nrf2^−/− mice.

^fThe significance of differences in the NAS scores of livers from RC-fed and HF-fed Nrf2^+/+ and Nrf2^−/− mice was assessed using the Kruskal-Wallis H test. The differences between the NAS results of the 4 experimental groups were highly significant (Kruskal-Wallis H test; P = 0.002), with both HF diet mice having higher NAS values than their chow-fed counterparts. Moreover, a significant difference was observed between the two HF-fed groups, with the Nrf2^−/− animals having the higher score (Kruskal-Wallis H test; P = 0.03), despite the fact that the steatosis components of NAS were similar in the two HF-fed groups, which blurs the difference in their NAS results. The difference in the NAS between HF-fed Nrf2^+/+ and Nrf2^−/− animals is smaller than the difference in inflammation and the degree of NASH between them; this represents a limitation of the NAS ranking system, which simply adds the 3 components together. Therefore, the apparent relative increase of steatosis in HF-fed Nrf2^+/+ livers compared to HF-fed Nrf2^−/− livers masks the increased inflammation score in the latter, because hepatocytes lose fat as they become inflamed. Fibrosis, which is not part of the NAS, was not observed in the livers of RC-fed animals or in HF-fed Nrf2^+/+ livers, but it was seen in HF-fed Nrf2^−/− livers (amounting to cirrhosis in 2 of 10 animals).