Background and Aims The hepatic mitogen‐activated protein kinase (MAPK) cascade leading to c‐Jun N‐terminal kinase (JNK) activation has been implicated in the pathogenesis of nonalcoholic fatty liver (NAFL)/NASH. In acute hepatotoxicity, we previously identified a pivotal role for mitochondrial SH3BP5 (SAB; SH3 homology associated BTK binding protein) as a target of JNK, which sustains its activation through promotion of reactive oxygen species production. Therefore, we assessed the role of hepatic SAB in experimental NASH and metabolic syndrome. Approach and Results In mice fed high‐fat, high‐calorie, high‐fructose (HFHC) diet, SAB expression progressively increased through a sustained JNK/activating transcription factor 2 (ATF2) activation loop. Inducible deletion of hepatic SAB markedly decreased sustained JNK activation and improved systemic energy expenditure at 8 weeks followed by decreased body fat at 16 weeks of HFHC diet. After 30 weeks, mice treated with control–antisense oligonucleotide (control‐ASO) developed steatohepatitis and fibrosis, which was prevented by Sab‐ASO treatment. Phosphorylated JNK (p‐JNK) and phosphorylated ATF2 (p‐ATF2) were markedly attenuated by Sab‐ASO treatment. After 52 weeks of HFHC feeding, control N‐acetylgalactosamine antisense oligonucleotide (GalNAc‐Ctl‐ASO) treated mice fed the HFHC diet exhibited progression of steatohepatitis and fibrosis, but GalNAc‐Sab‐ASO treatment from weeks 40 to 52 reversed these findings while decreasing hepatic SAB, p‐ATF2, and p‐JNK to chow‐fed levels. Conclusions Hepatic SAB expression increases in HFHC diet–fed mice. Deletion or knockdown of SAB inhibited sustained JNK activation and steatohepatitis, fibrosis, and systemic metabolic effects, suggesting that induction of hepatocyte Sab is an important driver of the interplay between the liver and the systemic metabolic consequences of overfeeding. In established NASH, hepatocyte‐targeted GalNAc‐Sab‐ASO treatment reversed steatohepatitis and fibrosis.

Pitx3 ak mice lack a functioning retina and develop fewer than 10% of dopamine neurons in the substantia nigra. Del Rı ´o-Martı ´n et al. ( 2019) reported that entrainment of circadian rhythms to daily light-dark (LD) cycles is absent in these mice, and that rhythms of locomotor activity, energy expenditure, and other metabolic variables are disrupted with food available ad libitum and fail to entrain to a daily feeding. The authors propose that retinal innervation of the suprachiasmatic nucleus is required for development of cyclic metabolic homeostasis, but methodological issues limit interpretation of the results. Using standardized feeding schedules and procedures for distinguishing free-running from entrained circadian rhythms, we confirm that behavioral and metabolic rhythms in Pitx3 ak mice do not entrain to LD cycles, but we find no impairment in circadian organization of metabolism with food available ad libitum and no impairment in entrainment of metabolic or behavioral rhythms by daily feeding schedules. This Matters Arising paper is in response to Del Rı ´o-Martı ´n et al. ( 2019), published in Cell Reports. See also the response by Fernandez-Perez et al. (2022), published in this issue.

Pitx3ak mice lack a functioning retina and nearly all dopamine neurons of the substantia nigra (SN). del Rio-Marten et al (2019) reported that entrainment of circadian rhythms to daily light-dark and feeding schedules is absent in these mice. With food limited to 12h/day, food anticipatory circadian rhythms failed to emerge, and metabolic rhythms failed to synchronize with locomotor and feeding rhythms. The authors propose that retinal innervation of the suprachiasmatic nucleus clock is required for development of cyclic metabolic homeostasis, but methodological issues limit interpretation of the results. Using standardized feeding schedules and procedures for distinguishing free-running from entrained circadian rhythms, we confirm that behavioral and metabolic rhythms in Pitx3ak mice do not entrain to LD cycles, but we find no desynchrony between these rhythms nor a deficit in entrainment to daily feeding schedules. SN dopamine neurons surviving in Pitx3ak mice may define a mininum population sufficient for food entrainment.

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