Sterol regulatory element binding protein-2 (SREBP-2) is activated by cytokines or pathogen, such as virus or bacteria, but its association with diminished cholesterol levels in COVID-19 patients is unknown. Here, we evaluated SREBP-2 activation in peripheral blood mononuclear cells of COVID-19 patients and verified the function of SREBP-2 in COVID-19. Intriguingly, we report the first observation of SREBP-2 C-terminal fragment in COVID-19 patients’ blood and propose SREBP-2 C-terminal fragment as an indicator for determining severity. We confirmed that SREBP-2-induced cholesterol biosynthesis was suppressed by Sestrin-1 and PCSK9 expression, while the SREBP-2-induced inflammatory responses was upregulated in COVID-19 ICU patients. Using an infectious disease mouse model, inhibitors of SREBP-2 and NF-κB suppressed cytokine storms caused by viral infection and prevented pulmonary damages. These results collectively suggest that SREBP-2 can serve as an indicator for severity diagnosis and therapeutic target for preventing cytokine storm and lung damage in severe COVID-19 patients.

Both glucose and free fatty acids (FFAs) are used as fuel sources for energy production in a living organism. Compelling evidence supports a role for excess fatty acids synthesized in intramuscular space or dietary intermediates in the regulation of skeletal muscle function. Excess FFA and lipid droplets leads to intramuscular accumulation of lipid intermediates. The resulting downregulation of the insulin signaling cascade prevents the translocation of glucose transporter to the plasma membrane and glucose uptake into skeletal muscle, leading to metabolic disorders such as type 2 diabetes. The mechanisms underlining metabolic dysfunction in skeletal muscle include accumulation of intracellular lipid derivatives from elevated plasma FFAs. This paper provides a review of the molecular mechanisms underlying insulin-related signaling pathways after excess accumulation of lipids.

Sterol regulatory element-binding protein (SREBP)-1c is involved in cellular lipid homeostasis and cholesterol biosynthesis and is highly increased in nonalcoholic steatohepatitis (NASH). However, the molecular mechanism by which SREBP-1c regulates hepatic stellate cells (HSCs) activation in NASH animal models and patients have not been fully elucidated. In this study, we examined the role of SREBP-1c in NASH and the regulation of LCN2 gene expression. Wild-type and SREBP-1c knockout (1cKO) mice were fed a high-fat/high-sucrose diet, treated with carbon tetrachloride (CCl₄), and subjected to lipocalin-2 (LCN2) overexpression. The role of LCN2 in NASH progression was assessed using mouse primary hepatocytes, Kupffer cells, and HSCs. LCN2 expression was examined in samples from normal patients and those with NASH. LCN2 gene expression and secretion increased in CCl₄-induced liver fibrosis mice model, and SREBP-1c regulated LCN2 gene transcription. Moreover, treatment with holo-LCN2 stimulated intracellular iron accumulation and fibrosis-related gene expression in mouse primary HSCs, but these effects were not observed in 1cKO HSCs, indicating that SREBP-1c-induced LCN2 expression and secretion could stimulate HSCs activation through iron accumulation. Furthermore, LCN2 expression was strongly correlated with inflammation and fibrosis in patients with NASH. Our findings indicate that SREBP-1c regulates Lcn2 gene expression, contributing to diet-induced NASH. Reduced Lcn2 expression in 1cKO mice protects against NASH development. Therefore, the activation of Lcn2 by SREBP-1c establishes a new connection between iron and lipid metabolism, affecting inflammation and HSCs activation. These findings may lead to new therapeutic strategies for NASH.

Cardiolipin, a unique phospholipid predominantly present in the inner mitochondrial membrane, is critical for maintaining mitochondrial integrity and function. Its dimeric structure and role in supporting mitochondrial dynamics, energy production, and mitophagy make it indispensable for skeletal muscle health. This review provides a comprehensive overview of cardiolipin biosynthesis, remodeling processes, and essential functions within mitochondria. We explore the influences of cardiolipin on the stability of the mitochondrial complexes, cristae formation, and calcium handling, all of which are vital for efficient oxidative phosphorylation and muscle contraction. Skeletal muscle, with its high energy demands, is particularly dependent on cardiolipin for optimal performance. We discuss the impact of aging on cardiolipin levels, which correlates with a decline in mitochondrial function and muscle mass, contributing to conditions such as sarcopenia. Furthermore, we examined the relationship between cardiolipin and endurance exercise, highlighting the effects of exercise-induced increase in cardiolipin levels on the improvement of mitochondrial function and muscle health. The role of Crls1 in cardiolipin synthesis has been emphasized as a potential therapeutic target for the treatment of sarcopenia. Increasing cardiolipin levels through gene therapy, pharmacological interventions, or specific exercise and nutritional strategies holds promise for mitigating muscle atrophy and promoting muscle regeneration. By focusing on the multifaceted role of cardiolipin in mitochondria and muscle health, we aimed to provide new insights into therapeutic approaches for enhancing muscle function and combating age-related muscle decline. Cardiolipin and Crls1 were reduced in aged skeletal muscle, contributing to mitochondrial dysfunction and muscle atrophy. In aged skeletal muscle, reduced CL levels are directly associated with impaired mitochondrial respiration capacity and structural degradation. Upregulating CL synthesis enhances mitochondrial function by stabilizing ETC proteins, increasing oxygen flux, and improving cristae architecture. Therapeutic strategies, including CL-targeting compounds like elamipretide and gene therapy, show promise for mitigating sarcopenia by improving mitochondrial bioenergetics and muscle regeneration.

Skeletal muscle aging results in the gradual suppression of myogenesis, leading to muscle mass loss. However, the specific role of cardiolipin in myogenesis has not been determined. This study investigated the crucial role of mitochondrial cardiolipin and cardiolipin synthase 1 (Crls1) in age-related muscle deterioration and myogenesis. Our findings demonstrated that cardiolipin and Crls1 are downregulated in aged skeletal muscle. Moreover, the knockdown of Crls1 in myoblasts reduced mitochondrial mass, activity, and OXPHOS complex IV expression and disrupted the structure of the mitochondrial cristae. AAV9-shCrls1-mediated downregulation of Crls1 impaired muscle regeneration in a mouse model of cardiotoxin (CTX)-induced muscle damage, whereas AAV9-mCrls1-mediated Crls1 overexpression improved regeneration. Overall, our results highlight that the age-dependent decrease in CRLS1 expression contributes to muscle loss by diminishing mitochondrial quality in skeletal muscle myoblasts. Hence, modulating CRLS1 expression is a promising therapeutic strategy for mitigating muscle deterioration associated with aging, suggesting potential avenues for developing interventions to improve overall muscle health and quality of life in elderly individuals.