Background and Aims: Mitochondrial antiviral signaling protein (MAVS) is a critical regulator that activates the host’s innate immunity against RNA viruses, and its signaling pathway has been linked to the secretion of proinflammatory cytokines. However, the actions of MAVS on inflammatory pathways during the development of metabolic dysfunction–associated steatotic liver disease (MASLD) have been little studied. Approach and Results: Liver proteomic analysis of mice with genetically manipulated hepatic p63, a transcription factor that induces liver steatosis, revealed MAVS as a target downstream of p63. MAVS was thus further evaluated in liver samples from patients and in animal models with MASLD. Genetic inhibition of MAVS was performed in hepatocyte cell lines, primary hepatocytes, spheroids, and mice. MAVS expression is induced in the liver of both animal models and people with MASLD as compared with those without liver disease. Using genetic knockdown of MAVS in adult mice ameliorates diet-induced MASLD. In vitro, silencing MAVS blunts oleic and palmitic acid–induced lipid content, while its overexpression increases the lipid load in hepatocytes. Inhibiting hepatic MAVS reduces circulating levels of the proinflammatory cytokine TNFα and the hepatic expression of both TNFα and NFκβ. Moreover, the inhibition of ERK abolished the activation of TNFα induced by MAVS. The posttranslational modification O-GlcNAcylation of MAVS is required to activate inflammation and to promote the high lipid content in hepatocytes. Conclusions: MAVS is involved in the development of steatosis, and its inhibition in previously damaged hepatocytes can ameliorate MASLD.

Weight gain is a hallmark of decreased estradiol (E2) levels because of menopause or following surgical ovariectomy (OVX) at younger ages. Of note, this weight gain tends to be around the abdomen, which is frequently associated with impaired metabolic homeostasis and greater cardiovascular risk in both rodents and humans. However, the molecular underpinnings and the neuronal basis for these effects remain to be elucidated. The aim of this study is to elucidate whether the kappa-opioid receptor (k-OR) system is involved in mediating body weight changes associated with E2 withdrawal. Here, we document that body weight gain induced by OVX occurs, at least partially, in a k-OR dependent manner, by modulation of energy expenditure independently of food intake as assessed in Oprk1−/−global KO mice. These effects were also observed following central pharmacological blockade of the k-OR system using the k-OR-selective antagonist PF-04455242 in wild type mice, in which we also observed a decrease in OVX-induced weight gain associated with increased UCP1 positive immunostaining in brown adipose tissue (BAT) and browning of white adipose tissue (WAT). Remarkably, the hypothalamic mTOR pathway plays an important role in regulating weight gain and adiposity in OVX mice. These findings will help to define new therapies to manage metabolic disorders associated with low/null E2 levels based on the modulation of central k-OR signaling.

Seipin, a protein encoded by the BSCL2 gene, plays a crucial role in lipid metabolism, and some pathogenic biallelic variants cause lipodystrophy and associated metabolic disorders. This study investigates liver pathology and dysregulation of the FGF21 signalling pathway in two mouse models: Bscl2^−/− (knock-out) and Bscl2^Celia/Celia (knock-in). We evaluated liver histopathology using H&E and Oil red O staining, assessed hepatic triglyceride levels via enzymatic assays, and analyzed gene expression of key FGF21-related components (Fgf21, Ppargc1a, Fgfr1, and Klb) using quantitative real-time PCR. The liver histology was scored using the NAFLD activity score (NAS) system. Both models exhibited hepatic steatosis and inflammatory features. The Bscl2^−/− mice showed more pronounced liver damage, including ballooning degeneration and fibrosis. Gene expression analysis revealed a significant increase in Fgf21 in both models, suggesting an adaptive response to liver injury. Notably, Fgfr1 and Ppargc1a expression was moderately elevated in severe neurologically affected mice showing less hepatic involvement, suggesting a potential adaptive or protective association of these genes with reduced steatosis. Seipin deficiency leads to metabolic-associated steatotic liver disease and dysregulated FGF21 signalling. These findings provide insight into the pathophysiological mechanisms of lipodystrophy and liver disease and suggest that the FGF21 pathway could be a therapeutic target for treating seipin-related metabolic disorders.

Background/Objectives: Asprosin is the endogenous ligand of the olfactory Olfr734 receptor linked to MASLD and glucose metabolism. Despite the involvement of asprosin in these processes, little has been published on the specific role of Olfr734 in liver function. The aim of this work is therefore to study the specific role of the olfactory Olfr734 receptor in MASLD and glucose metabolism. Methods: To achieve this objective, we performed a genetic inhibition specifically to inhibit Olfr734 in the livers of male mice. We then studied the progression of MASLD in DIO mice. In addition, we studied the glucose metabolism in hypoglycemia states and postprandial glucose production in standard diet-fed mice. Finally, analyses of liver biopsies from patients with obesity and with or without T2DM were conducted. Results: We found that hepatic Olfr734 levels vary according to changes in nutritional status and its knockdown effect in the liver is to increase the hepatic lipid content in DIO mice. Our results also showed that OLFR734 expression is involved in the adaptive response in terms of glucose production to nutrient availability. Finally, the hepatic human Olfr734 ortholog named OR4M1 has been observed to be at significantly higher levels in male patients with T2DM. Conclusions: This study increases understanding of the mechanisms by which the modulation of Olfr734 expression affects liver function.