Suppression of hepatic ChREBP⍺-CYP2C50 axis-driven fatty acid oxidation sensitizes mice to diet-induced MASLD/MASH.

Compromised hepatic fatty acid oxidation (FAO) has been observed in human MASH patients and animal models of MASLD/MASH. It remains poorly understood how and when the hepatic FAO pathway is suppressed during the progression of MASLD towards MASH. Hepatic ChREBP⍺ is a classical lipogenic transcription factor that responds to the intake of dietary sugars. We examined its role in regulating hepatocyte fatty acid oxidation (FAO) and the impact of hepatic Chrebpa deficiency on sensitivity to diet-induced MASLD/MASH in mice. We discovered that hepatocyte ChREBP⍺ is both necessary and sufficient to maintain FAO in a cell-autonomous manner independently of its DNA-binding activity. Supplementation of synthetic PPAR⍺/δ agonist is sufficient to restore FAO in Chrebp-/- primary mouse hepatocytes. Hepatic ChREBP⍺ was decreased in mouse models of diet-induced MAFSLD/MASH and in patients with MASH. Hepatocyte-specific Chrebp⍺ knockout impaired FAO, aggravated liver steatosis and inflammation, leading to early-onset fibrosis in response to diet-induced MASH. Conversely, liver overexpression of ChREBP⍺-WT or its non-lipogenic mutant enhanced FAO, reduced lipid deposition, and alleviated liver injury, inflammation, and fibrosis. RNA-seq analysis identified the CYP450 epoxygenase (CYP2C50) pathway of arachidonic acid metabolism as a novel target of ChREBP⍺. Over-expression of CYP2C50 partially restores hepatic FAO in primary hepatocytes with Chrebp⍺ deficiency and attenuates preexisting MASH in the livers of hepatocyte-specific Chrebp⍺-deleted mice. Our findings support the protective role of hepatocyte ChREBPa against diet-induced MASLD/MASH in mouse models in part via promoting CYP2C50-driven FAO.

Zhang D ，Zhao Y ，Zhang G ，Lank D ，Cooke S ，Wang S ，Nuotio-Antar A ，Tong X ，Yin L ... -  《Molecular Metabolism》

Hepatic Deletion of Carbohydrate Response Element Binding Protein Impairs Hepatocarcinogenesis in a High-Fat Diet-Induced Mouse Model.

Karim M ，Prey J ，Willer F ，Leiner H ，Yasser M ，Dombrowski F ，Ribback S ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

ACMSD inhibition corrects fibrosis, inflammation, and DNA damage in MASLD/MASH.

Recent findings reveal the importance of tryptophan-initiated de novo nicotinamide adenine dinucleotide (NAD+) synthesis in the liver, a process previously considered secondary to biosynthesis from nicotinamide. The enzyme α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), primarily expressed in the liver and kidney, acts as a modulator of de novo NAD+ synthesis. Boosting NAD+ levels has previously demonstrated remarkable metabolic benefits in mouse models. In this study, we aimed to investigate the therapeutic implications of ACMSD inhibition in the treatment of metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH). In vitro experiments were conducted in primary rodent hepatocytes, Huh7 human liver carcinoma cells and induced pluripotent stem cell-derived human liver organoids (HLOs). C57BL/6J male mice were fed a western-style diet and housed at thermoneutrality to recapitulate key aspects of MASLD/MASH. Pharmacological ACMSD inhibition was given therapeutically, following disease onset. HLO models of steatohepatitis were used to assess the DNA damage responses to ACMSD inhibition in human contexts. Inhibiting ACMSD with a novel specific pharmacological inhibitor promotes de novo NAD+ synthesis and reduces DNA damage ex vivo, in vivo, and in HLO models. In mouse models of MASLD/MASH, de novo NAD+ biosynthesis is suppressed, and transcriptomic DNA damage signatures correlate with disease severity; in humans, Mendelian randomization-based genetic analysis suggests a notable impact of genomic stress on liver disease susceptibility. Therapeutic inhibition of ACMSD in mice increases liver NAD+ and reverses MASLD/MASH, mitigating fibrosis, inflammation, and DNA damage, as observed in HLO models of steatohepatitis. Our findings highlight the benefits of ACMSD inhibition in enhancing hepatic NAD+ levels and enabling genomic protection, underscoring its therapeutic potential in MASLD/MASH. Enhancing NAD+ levels has been shown to induce remarkable health benefits in mouse models of metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH), yet liver-specific NAD+ boosting strategies remain underexplored. Here, we present a novel pharmacological approach to enhance de novo synthesis of NAD+ in the liver by inhibiting α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), an enzyme highly expressed in the liver. Inhibiting ACMSD increases NAD+ levels, enhances mitochondrial respiration, and maintains genomic stability in hepatocytes ex vivo and in vivo. These molecular benefits prevent disease progression in both mouse and human liver organoid models of steatohepatitis. Our preclinical study identifies ACMSD as a promising target for MASLD/MASH management and lays the groundwork for developing ACMSD inhibitors as a clinical treatment.

Liu YJ ，Kimura M ，Li X ，Sulc J ，Wang Q ，Rodríguez-López S ，Scantlebery AML ，Strotjohann K ，Gallart-Ayala H ，Vijayakumar A ，Myers RP ，Ivanisevic J ，Houtkooper RH ，Subramanian GM ，Takebe T ，Auwerx J ... -  《-》

Hinokitiol ameliorates MASH in mice by therapeutic targeting of hepatic Nrf2 and inhibiting hepatocyte ferroptosis.

Metabolic dysfunction-associated steatohepatitis (MASH), an advanced stage of metabolic dysfunction-associated steatotic liver disease (MASLD), still lacks approved effective clinical drugs. Ferroptosis, a form of regulated cell death driven by excessive iron accumulation and uncontrollable lipid peroxidation, has been proven to be a trigger of inflammation and initiation of steatohepatitis. The pathogenic interplay is modulated by oxidative stress, while the Nrf2-mediated antioxidant response plays a regulatory role in ferroptosis. Phytochemical hinokitiol (Hino) has demonstrated positive efficacy in hepatocellular carcinoma (HCC) in the reported work, but it remains unknown whether its therapeutic effect attributes to delaying the progress of steatohepatitis to HCC. This work aimed to systemically investigate the significance of ferroptosis in the pathogenesis of MASH and to demonstrate that Hino, a bioactive monoterpene compound, attenuates the primary pathological characteristics of MASH via promotion of Nrf2/GPX4 signaling. In this work, a MASH model was established using the high-fat/high-cholesterol (HFHC) diet-fed in vivo and palmitic acid/oleic acid (PO)-stimulated hepatocytes in vitro. Biochemical indexes, pathological analysis, western blot, PCR assay, energy metabolic phenotype, molecular docking, and confirmatory assays were performed comprehensively to reveal the key link between the Nrf2/GPX4 axis and the treatment of MASH. Under MASH conditions with increased oxidative stress, we show that Nrf2 was remarkable downregulated in HFHC diet-fed mice and PO-managed hepatocytes. Mechanistically, hepatic upregulation of Nrf2 through phytochemical Hino supplementation inhibited ferroptosis, enhanced lipid metabolism, and thereby alleviated hepatic steatosis, inflammation, and fibrosis. Conversely, silencing Nrf2 in hepatocytes further promoted the accumulation of key markers of ferroptosis and aggravated MASH phenotypes. Increased ferroptosis promoted steatosis which further drove inflammation and hepatic fibrosis. Our results suggested the significance of Nrf2 in ameliorating MASH, which was regulated through Hino. Thus, targeted inhibition of ferroptosis through Hino administration is a feasible and effective approach for treating MASH.

Yin X ，Liu Z ，Li C ，Wang J ... -  《-》

Cinnabarinic acid protects against metabolic dysfunction-associated steatohepatitis by activating aryl hydrocarbon receptor-dependent AMPK signaling.

Patil NY ，Rus I ，Ampadu F ，Abu Shukair HM ，Bonvicino S ，Brush RS ，Eaton E ，Agbaga MP ，Oh TG ，Friedman JE ，Joshi AD ... -  《-》