Phenobarbital, a hepatic metabolic enzyme inducer, inhibits preneoplastic hepatic lesions with expression of selective autophagy receptor p62 and ER-phagy receptor FAM134B in high-fat diet-fed rats through the inhibition of ER stress

We investigated the role of endoplasmic reticulum (ER)-phagy in NAFLD-related hepatocarcinogenesis in high-fat diet (HFD)-fed and/or phenobarbital (PB)-treated rats by clustering the expression levels of the selective autophagy receptor p62 and the ER-phagy-specific receptor FAM134B in preneoplastic hepatic lesions. We obtained four clusters with variable expression levels of p62 and FAM134B in preneoplastic lesions, and a variable population of clusters in each group. PB administration increased the clusters with high expression levels of p62 while HFD feeding increased the clusters with high expression levels of both p62 and FAM134B. The areas of preneoplastic lesions of these clusters were significantly increased than those of other clusters with low expression levels of p62 and FAM134B. The combination of HFD feeding with PB counteracted the effects of each other, and the cluster composition was similar to that in the control group. The results were associated with decreased gene expression of ER stress, inflammatory cytokine, autophagy, and increased expression of antioxidant enzyme. The present study demonstrated that clustering analysis is useful for understanding the role of autophagy in each preneoplastic lesion, and that HFD feeding increased preneoplastic lesions through the inhibition of ER-phagy, which was cancelled with PB administration through the induction of ER-phagy.