Hepatic Mitochondrial SAB Deletion or Knockdown Alleviates Diet‐Induced Metabolic Syndrome, Steatohepatitis, and Hepatic Fibrosis

Abstract

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.

Single-Cell Sequencing Revealed Pivotal Genes Related to Prognosis of Myocardial Infarction Patients

“…The loss of RINT1 affects the fate of PDAC cells by interfering with the SUMOylation pathway, and in acute liver toxicity [41,42]. In acute hepatotoxicity, mitochondrial SH3BP5, as the target of JNK, maintains its activation by promoting the production of reactive oxygen species [43]. The overexpression of Slc43a3 reduces FA uptake in differentiated OP9 cells and leads to reduced lipid droplet accumulation [44].…”

Mechanism and Therapeutic Targets of c-Jun-N-Terminal Kinases Activation in Nonalcoholic Fatty Liver Disease

“…As an example, JNK targeted GCLC are ubiquitinated and degraded leading to decreased GSH level and increased oxidative stress as occur in the acute acetaminophen hepatotoxicity [ 64 , 77 ]. In NASH, P-JNK targeting of transcriptional factors, such as SREBFs to increase lipogenesis and cholesterol synthesis, NCoR1 to repress PPARα and fatty acid oxidation, leads to cumulative lipotoxic stress [ 78 , 79 , 80 ]. Therefore, P-JNK-SAB ROS activation loop is a key mediator in sustained activation of JNK.…”

“…Hepatic fat is mostly triglyceride formed by esterification of free fatty acid from the diet, adipose tissue lipolysis and de novo lipogenesis. Fat accumulation in hepatocytes causes lipotoxicity and apoptosis [ 6 , 16 , 53 ] and ballooning degeneration of hepatocytes which are associated with oxidative stress in steatosis/steatohepatitis [ 78 ]. In the course of disease progression, high calorie diet increases mitochondrial function and metabolism accompanied with stress kinase activation [ 78 , 81 ].…”

Detailed Molecular Mechanisms Involved in Drug-Induced Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis: An Update

“…JNK-induced SAB phosphorylation promotes mitochondrial dysfunction and ROS production and, as a feedback reaction, it activates the upstream mitogen-activated protein kinase (MAPK) pathway, which is the initial event in the P-JNK-mitoSAB-ROS activation loop [ 126 , 127 , 128 ]. In addition, studies in mice fed by high-fat, high calorie and high-fructose (HFHC) diet demonstrated a time-dependent increase in SAB expression, with the concomitant JNK activation [ 129 ]. The same authors also demonstrated that inducible hepatocyte specific SAB deletion (Sabi∆Hep) in mice reduced significantly the JNK activation after 8 weeks of HFHC diet, accompanied by decreased body fat after 16 weeks.…”

“…Similar data were obtained in 40-week-HFHC fed mice treated with SAB N-acetylgalactosamine antisense oligonucleotide (GalNAc-Sab-ASO) to obtain SAB knockdown mice. SAB knockdown mice, after 40 to 52 weeks of HFHC diet, showed a decreased steatohepatitis and fibrosis and restored SAB and P-JNK levels, with respect to those found in mice fed by standard diet, demonstrating the crucial role of P-JNK-mitoSAB-ROS loop in NASH [ 129 ].…”