Inhibition of mTOR improves malnutrition induced hepatic metabolic dysfunction

Abstract

Severe malnutrition accounts for half-a-million deaths annually in children under the age of five. Despite improved WHO guidelines, inpatient mortality remains high and is associated with metabolic dysfunction. Previous studies suggest a correlation between hepatic metabolic dysfunction and impaired autophagy. We aimed to determine the role of mTORC1 inhibition in a murine model of malnutrition-induced hepatic dysfunction. Wild type weanling C57/B6 mice were fed a 18 or 1% protein diet for two weeks. A third low-protein group received daily rapamycin injections, an mTORC1 inhibitor. Hepatic metabolic function was assessed by histology, immunofluorescence, gene expression, metabolomics and protein levels. Low protein-fed mice manifested characteristics of severe malnutrition, including weight loss, hypoalbuminemia, hypoglycemia, hepatic steatosis and cholestasis. Low protein-fed mice had fewer mitochondria and showed signs of impaired mitochondrial function. Rapamycin prevented hepatic steatosis, restored ATP levels and fasted plasma glucose levels compared to untreated mice. This correlated with increased content of LC3-II, and decreased content mitochondrial damage marker, PINK1. We demonstrate that hepatic steatosis and disturbed mitochondrial function in a murine model of severe malnutrition can be partially prevented through inhibition of mTORC1. These findings suggest that stimulation of autophagy could be a novel approach to improve metabolic function in severely malnourished children.

Modified Linggui Zhugan Decoction protects against ventricular remodeling through ameliorating mitochondrial damage in post-myocardial infarction rats

“…Previous reports suggest that PPAR-γ activation increased MMP and protected cells from apoptosis ( 95 ). Mitochondrial electron transport chain complex I and IV, COX IV content, along with ATP, are regarded as markers of mitochondrial function ( 96 , 97 ), and COX IV is a classic enzyme marker of electron transport chain ( 97 ). In the present experiment, abnormal mitochondrial morphologies, increased mitochondrial numbers, decreased mitochondrial areas, disturbed expression of Mfn2, p-Drp1 or Drp1, PGC-1α, PPAR-γ, and COX IV induced by MI or OGD, were ameliorated through MLZD administration.…”

DNA Methylation of Genes Participating in Hepatic Metabolisms and Function in Fetal Calf Liver Is Altered by Maternal Undernutrition during Gestation

“…This was further supported by the downregulation of NTHL1 , a mitochondrial DNA glycosylase, which was downregulated due to MUN. Low PINK1 expression may be induced by mTOR signaling activity originating from upstream GF and hormone signals [ 65 ]. The notable abundance of DM hepatic genes encoding key mitochondrial metabolic enzymes ( PC , TAT , ACAD8 , PINK1 , and NTHL1 ) is a noteworthy finding that highlights the central role of mitochondria in metabolic adaptations in response to nutritional stress in the fetal liver.…”

Rebalancing of mitochondrial homeostasis through an NAD+-SIRT1 pathway preserves intestinal barrier function in severe malnutrition

“…This study aimed to reveal whether the tryptophan-NAD + -SIRT1 and autophagy pathways are involved in the aetiology of SM-induced enteropathy and whether modulating these pathways can protect intestinal structure and function. Using mouse and organoid models of malnutrition induced enteropathy, 22 , 23 we discovered that low plasma tryptophan was associated with a reduction in SIRT1 mediated mitochondrial biogenesis and autophagy activity. We demonstrated the therapeutic potential of NAM in ameliorating malnutrition enteropathy and showed that regenerating NAD + through the NAD + -salvage pathway with NAM supplementation improved autophagy, intestinal barrier function, and mitochondrial damage.…”