Aberrant hepatocyte Notch activity is critical to the development of nonalcoholic steatohepatitis (NASH)–induced liver fibrosis, but mechanisms underlying Notch reactivation in developed liver are unclear. Here, we identified that increased expression of the Notch ligand Jagged1 (JAG1) tracked with Notch activation and nonalcoholic fatty liver disease (NAFLD) activity score (NAS) in human liver biopsy specimens and mouse NASH models. The increase in Jag1 was mediated by hepatocyte Toll-like receptor 4 (TLR4)–nuclear factor κB (NF-κB) signaling in pericentral hepatocytes. Hepatocyte-specific Jag1 overexpression exacerbated fibrosis in mice fed a high-fat diet or a NASH-provoking diet rich in palmitate, cholesterol, and sucrose and reversed the protection afforded by hepatocyte-specific TLR4 deletion, whereas hepatocyte-specific Jag1 knockout mice were protected from NASH-induced liver fibrosis. To test therapeutic potential of this biology, we designed a Jag1-directed antisense oligonucleotide (ASO) and a hepatocyte-specific N-acetylgalactosamine (GalNAc)–modified siRNA, both of which reduced NASH diet–induced liver fibrosis in mice. Overall, these data demonstrate that increased hepatocyte Jagged1 is the proximal hit for Notch-induced liver fibrosis in mice and suggest translational potential of Jagged1 inhibitors in patients with NASH.

Posttranslational modification of proteins via ubiquitination determines their activation, translocation, dysregulation, or degradation. This process targets a large number of cellular proteins, affecting all biological pathways involved in the cell cycle, development, growth, and differentiation. Thus, aberrant regulation of ubiquitination is likely associated with several diseases, including various types of metabolic diseases. Among the ubiquitin enzymes, E3 ubiquitin ligases are regarded as the most influential ubiquitin enzymes due to their ability to selectively bind and recruit target substrates for ubiquitination. Continued research on the regulatory mechanisms of E3 ligases and their adaptors in metabolic diseases will further stimulate the discovery of new targets and accelerate the development of therapeutic options for metabolic diseases. In this review, based on recent discoveries, we summarize new insights into the roles of E3 ubiquitin ligases and their adaptors in the pathogenesis of metabolic diseases by highlighting recent evidence obtained in both human and animal model studies.

Su Jin Hwang, Geun-Hyoung Ha, Woo-Young Seo, Chung Kwon Kim, KyeongJin Kim & Sang Bae Lee. BMB Reports 2020;53:539-44. https://doi.org/10.5483/BMBRep.2020.53.10.120

Su Jin Hwang, Su Hwan Kim, Woo-Young Seo, Yelin Jeong, Min Cheol Shin, Dongryeol Ryu, Sang Bae Lee, Young Jin Choi & KyeongJin Kim. BMB Reports 2021;54:329-34. https://doi.org/10.5483/BMBRep.2021.54.6.038

Semaglutide has recently received conditional accelerated approval in the US for treatment of metabolic dysfunction‐associated steatohepatitis (MASH) with significant or advanced liver fibrosis (stage F2/F3). Phase 2 and 3 clinical trials show that subcutaneous semaglutide 2.4 mg/week leads to significant improvements in hepatic steatosis, disease activity, resolution of MASH and reduction in liver fibrosis. These benefits parallel weight loss and are accompanied by improved metabolic outcomes, including better glucose control and lipid profiles, as well as consistent benefits for cardiovascular and renal health. The treatment's safety profile is manageable, with gastrointestinal issues being the most frequent side effects, and no new safety concerns have been identified. Data on long‐term tolerability, treatment retention and clinical events are now awaited in people with MASH fibrosis. The evidence regarding semaglutide's ability to directly target the liver and improve liver damage in cirrhosis, and its impact on muscle mass in at‐risk populations, remains limited. Thus, in patients with advanced disease, it should be viewed primarily as a therapy that modifies metabolic disease. Practically, semaglutide is most suitable as a first‐line treatment to prevent liver complications for people with MASH and stage F2/F3 fibrosis with severe metabolic dysfunction, obesity, or type 2 diabetes who could benefit from both liver and cardiovascular‐renal improvements. Treatment should be tailoured to each individual, with ongoing monitoring of body weight, serum aminotransferase levels and direct measurement of liver fat and stiffness to guide therapy.

Increased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice.A-PHLPP2mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fedA-PHLPP2mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.