Current treatment paradigms for metabolic dysfunction-associated steatohepatitis (MASH) are based primarily on dietary restrictions and the use of existing drugs, including anti-diabetic and anti-obesity medications. However, given the limited number of approved drugs specifically for MASH, recent efforts have focused on promising strategies that specifically target hepatic lipid metabolism, inflammation, fibrosis, or a combination of these processes. In this review, we examined the pathophysiology underlying the development of MASH in relation to recent advances in effective MASH therapy. Particularly, we analyzed the effects of lipogenesis inhibitors, nuclear receptor agonists, glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists, fibroblast growth factor mimetics, and combinatorial therapeutic approaches. We summarize these targets along with their preclinical and clinical candidates with the ultimate goal of optimizing the therapeutic prospects for MASH.
Obesity is considered an epidemic often accompanied by insulin resistance (IR). Heat treatment (HT) has been shown to prevent high-fat diet-induced IR in skeletal muscle, but the underlying mechanisms are poorly understood. In this study, we discovered that high temperature alleviated the hallmarks of obesity by promoting glycogen synthesis and lowering blood glucose levels in skeletal muscle tissue (SMT). Additionally, HT maintained the decay phase of heat shock factor 1 (HSF1), leading to the activation of gene expression of heat shock proteins (HSPs), which contributed to the alleviation of IR in SMT of diet-induced obese (DIO) mice. Metabolomics and lipidomics analyses showed that HT promoted ceramide (Cer) breakdown, resulting in an elevation of both sphingomyelin (SM) and sphingosine, which further contributed to the amelioration of IR in SMT of DIO mice. Importantly, the increase in sphingosine was attributed to the heightened expression of the acid ceramidase N-acylsphingosine amidohydrolase 1 (ASAH1), and the inhibition of ASAH1 attenuated HT-relieved IR in SMT of DIO mice. Surprisingly, high temperature increased the composition of Cer and cholesteryl ester in lipid droplets of skeletal muscle cells. This not only helped alleviate IR but also prevented lipotoxicity in SMT of DIO mice. These findings revealed a previously unknown connection between a high-temperature environment and sphingolipid metabolism in obesity, suggesting that high temperature can improve IR by promoting Cer catabolism in SMT of obese mice.
Ningning Liang, Xuan Yuan, Lili Zhang, Xia Shen, Shanshan Zhong, Luxiao Li, Rui Li, Xiaodong Xu, Xin Chen, Chunzhao Yin, Shuyuan Guo, Jing Ge, Mingjiang Zhu, Yongzhen Tao, Shiting Chen, Yongbing Qian, Nicola Dalbeth, Tony R Merriman, Robert Terkeltaub, Changgui Li, Qiang Xia, Huiyong Yin·17 May 2024
loae018
Dyslipidemia affects approximately half of all people with gout, and prior Mendelian randomization analysis suggested a causal role for elevated triglycerides in hyperuricemia (HU), but the underlying mechanisms remain elusive. We hypothesize that dyslipidemia promotes hepatic urate biosynthesis in HU and gout and fatty acid (FA) oxidation (FAO) drives this process. Here we developed a targeted metabolomics to quantify major metabolites in purine metabolic pathway in the sera of a human cohort with HU, gout, and normaluricemic controls. We found that the levels of major purine metabolites and multiple FAs were significantly elevated in HU and gout, compared to normouricemic controls, whereas hypoxathine showed opposite trend. Furthermore, the levels of multiple serum FAs were positively correlated with urate, xanthine, and inosine but negatively with hypoxanthine, which was also observed in a murine model of high-fat diet-induced HU. Using a stable isotope labeled metabolic flux assay, we discovered that exogenous hypoxanthine plays a key role in urate synthesis. Moreover, FAO-induced hypoxia-inducible factor 1 alpha (HIF-1α) activation upregulated 5’-nucleotidase II (NT5C2) and xanthine dehydrogenase (XDH) levels to facilitate hypoxanthine uptake from blood to liver and activation of urate biosynthesis. Our findings was further supported by data in human hepatocytes and 50 paired serum and liver tissues from liver transplant donors.Together, this study uncovers a mechanism by which FAO promotes hepatic urate synthesis by activating HIF-1α-NT5C2/XDH pathways, directly linking lipid metabolism to HU.
Understanding sex disparities in modifiable risk factors across the lifespan is essential for crafting individualized intervention strategies. We aim to investigate the age-related sex disparity in cardiometabolic phenotypes in a large nationwide Chinese cohort. A total of 254,670 adults aged 40 years or older were selected from a population-based cohort in China. Substantial sex disparities in the prevalence of metabolic diseases were observed across different age strata, particularly for dyslipidemia and its components. Generalized additive models were employed to characterize phenotype features, elucidating how gender differences evolve with advancing age. Half of the 16 phenotypes, consistently exhibited no sex differences, while four (HDL cholesterol, apolipoprotein A1, diastolic blood pressure, and fasting insulin) displayed significant sex differences across all age groups. Triglycerides, apolipoprotein B, non-HDL, and total cholesterol demonstrated significant age-dependent sex disparities. Notably, pre-menopausal females exhibited significant age-related differences in lipid levels around age 40-50, contrasting with the relatively stable associations observed in males and post-menopausal females. Menopause played an important but not sole role in age-related sex differences in blood lipids. Sleep duration also had an age- and sex-dependent impact on lipids. Lipidomic analysis and K-means clustering further revealed that 58.6% of the 263 measured lipids, varied with sex and age, with sphingomyelins, cholesteryl esters, and triacylglycerols being the most profoundly influenced lipid species by the combined effects of age, sex, and their interaction. These findings underscore the importance of age consideration when addressing gender disparities in metabolic diseases and advocate for personalized, age-specific prevention and management.
