Lactate is an end product of glycolysis. As a critical energy source for mitochondrial respiration, lactate also acts as a precursor of gluconeogenesis and a signaling molecule. We briefly summarize emerging concepts regarding lactate metabolism, such as the lactate shuttle, lactate homeostasis, and lactate-microenvironment interaction. Accumulating evidence indicates that lactate-mediated reprogramming of immune cells and enhancement of cellular plasticity contribute to establishing disease-specific immunity status. However, the mechanisms by which changes in lactate states influence the establishment of diverse functional adaptive states are largely uncharacterized. Posttranslational histone modifications create a code that functions as a key sensor of metabolism and are responsible for transducing metabolic changes into stable gene expression patterns. In this review, we describe the recent advances in a novel lactate-induced histone modification, histone lysine lactylation. These observations support the idea that epigenetic reprogramming-linked lactate input is related to disease state outputs, such as cancer progression and drug resistance.

Non-alcoholic fatty liver disease (NAFLD) is an important health issue worldwide. We aimed to develop a simple model to determine the presence of NAFLD in a Chinese population. A cross-sectional study with 9602 subjects was conducted. Potential predictors were entered into a stepwise logistic regression analysis to obtain the model. We used 148 patients with liver biopsy to validate this model. The model, named the ZJU index, was developed based on body mass index (BMI), fasting plasma glucose (FPG), triglycerides (TG) and the serum alanine aminotransferase (ALT) to serum aspartate transaminase (AST) ratio. The area under the receiver operating characteristic curve (AUROC) of the ZJU index to detect NAFLD was 0.822. At a value of 38.0, the ZJU index could detect NAFLD with a specificity of 93.4%. In patients with liver biopsy, the ZJU index could detect steatosis with good accuracy, with an AUROC of 0.896. This study revealed that the ZJU index is a helpful model to detect NAFLD for community physicians in China. It was validated not only by a validation cohort but also by pathological data.

Objective: Accumulation of free fatty acids (FFAs) in hepatocytes induces lipotoxicity, leading to non-alcoholic fatty liver disease (NAFLD). This study aimed to investigate the underlying mechanisms by which FFA contributes to the pathogenesis of NAFLD via the regulation of 3-mercaptopyruvate sulfurtransferase (MPST), a key enzyme that regulates endogenous hydrogen sulfide (H ₂ S) biosynthesis. Design: Hepatic MPST expression was evaluated in mice and patients with NAFLD. A variety of molecular approaches were used to study the effects of MPST regulation on hepatic steatosis in vivo and in vitro. Results: In vitro treatment of hepatocytes with FFAs upregulated MPST expression, which was partially dependent on NF-κB/p65. Hepatic MPST expression was markedly increased in high fat diet (HFD)-fed mice and patients with NAFLD. Partial knockdown of MPST via adenovirus delivery of MPST short hairpin RNA or heterozygous deletion of the Mpst gene significantly ameliorated hepatic steatosis in HFD-fed mice. Consistently, inhibition of MPST also reduced FFA-induced fat accumulation in L02 cells. Intriguingly, inhibition of MPST significantly enhanced rather than decreased H ₂ S production, whereas MPST overexpression markedly inhibited H ₂ S production. Co-immunoprecipitation experiments showed that MPST directly interacted with and negatively regulated cystathionine γ-lyase (CSE), a major source of H ₂ S production in the liver. Mechanistically, MPST promoted steatosis via inhibition of CSE/H ₂ S and subsequent upregulation of the sterol regulatory element-binding protein 1c pathway, C-Jun N-terminal kinase phosphorylation and hepatic oxidative stress. Conclusions: FFAs upregulate hepatic expression of MPST and subsequently inhibit the CSE/H ₂ S pathway, leading to NAFLD. MPST may be a potential therapeutic target for NAFLD.

The increasing prevalence of metabolic syndrome has become a serious public health problem. Certain bacteria-derived metabolites play a key role in maintaining human health by regulating the host metabolism. Recent evidence shows that indole-3-propionic acid content can be used to predict the occurrence and development of metabolic diseases. Supplementing indole-3-propionic acid can effectively improve metabolic disorders and is considered a promising metabolite. Therefore, this article systematically reviews the latest research on indole-3-propionic acid and elaborates its source of metabolism and its association with metabolic diseases. Indole-3-propionic acid can improve blood glucose and increase insulin sensitivity, inhibit liver lipid synthesis and inflammatory factors, correct intestinal microbial disorders, maintain the intestinal barrier, and suppress the intestinal immune response. The study of the mechanism of the metabolic benefits of indole-3-propionic acid is expected to be a potential compound for treating metabolic syndrome.