Zinc finger protein ZNF638 regulates triglyceride metabolism via ANGPTL8 in an estrogen dependent manner.

BACKGROUND AND AIM: Triglyceride (TG) levels are closely related to obesity, fatty liver and cardiovascular diseases, while the regulatory factors and mechanism for triglyceride homeostasis are still largely unknown. Zinc Finger Protein 638 (ZNF638) is a newly discovered member of zinc finger protein family for adipocyte function in vitro. The aim of the present work was to investigate the role of ZNF638 in regulating triglyceride metabolism in mice. METHODS: We generated ZNF638 adipose tissue specific knockout mice (ZNF638 FKO) by cross-breeding ZNF638 flox to Adiponectin-Cre mice and achieved adipose tissue ZNF638 overexpression via adenoviral mediated ZNF638 delivery in inguinal adipose tissue (iWAT) to examined the role and mechanisms of ZNF638 in fat biology and whole-body TG homeostasis. RESULTS: Although ZNF638 FKO mice showed similar body weights, body composition, glucose metabolism and serum parameters compared to wild-type mice under chow diet, serum TG levels in ZNF638 FKO mice were increased dramatically after refeeding compared to wild-type mice, accompanied with decreased endothelial lipoprotein lipase (LPL) activity and increased lipid absorption of the small intestine. Conversely, ZNF638 overexpression in iWAT reduced serum TG levels while enhanced LPL activity after refeeding in female C57BL/6J mice and obese ob/ob mice. Specifically, only female mice exhibited altered TG metabolism upon ZNF638 expression changes in fat. Mechanistically, RNA-sequencing analysis revealed that the TG regulator angiopoietin-like protein 8 (Angptl8) was highly expressed in iWAT of female ZNF638 FKO mice. Neutralizing circulating ANGPTL8 in female ZNF638 FKO mice abolished refeeding-induced TG elevation. Furthermore, we demonstrated that ZNF638 functions as a transcriptional repressor by recruiting HDAC1 for histone deacetylation and broad lipid metabolic gene suppression, including Angptl8 transcription inhibition. Moreover, we showed that the sexual dimorphism is possibly due to estrogen dependent regulation on ZNF638-ANGPTL8 axis. CONCLUSION: We revealed a role of ZNF638 in the regulation of triglyceride metabolism by affecting Angptl8 transcriptional level in adipose tissue with sexual dimorphism.

Ootheca mantidis mitigates renal fibrosis in mice by the suppression of apoptosis via increasing the gut microbe Akkermansia muciniphila and modulating glutamine metabolism.

Renal interstitial fibrosis (RIF), a progressive process affecting the kidneys in chronic kidney disease (CKD), currently lacks an effective therapeutic intervention. Traditional Chinese medicine (TCM) has shown promise in reducing RIF and slowing CKD progression. In this study, we demonstrated the dose-dependent attenuation of RIF by Ootheca mantidis (SPX), a commonly prescribed TCM for CKD, in a mouse model of unilateral ureteral obstruction (UUO). RNA-sequencing analysis suggested that SPX treatment prominently downregulated apoptosis and inflammation-associated pathways, thereby inhibiting the fibrogenic signaling in the kidney. We further found that transplantation of fecal microbiota from SPX-treated mice conferred protection against renal injury and fibrosis through suppressing apoptosis in UUO mice, indicating that SPX ameliorated RIF via remodeling the gut microbiota and reducing apoptosis in the kidneys. Further functional exploration of the gut microbiota combined with fecal metabolomics revealed increased levels of some probiotics, including Akkermansia muciniphila (A. muciniphila), and modulations in glutamine-related amino acid metabolism in UUO mice treated with SPX. Subsequent colonization of A. muciniphila and supplementation with glutamine effectively mitigated cell apoptosis and RIF in UUO mice. Collectively, these findings unveil a functionally A. muciniphila- and glutamine-involved gut-renal axis that contributes to the action of SPX, and provide important clue for the therapeutic potential of SPX, A. muciniphila, and glutamine in combatting RIF.

Glycine-ß-muricholic acid antagonizes the intestinal farnesoid X receptor-ceramide axis and ameliorates NASH in mice.

Nonalcoholic steatohepatitis (NASH) is a rapidly developing pathology around the world, with limited treatment options available. Some farnesoid X receptor (FXR) agonists have been applied in clinical trials for NASH, but side effects such as pruritus and low-density lipoprotein elevation have been reported. Intestinal FXR is recognized as a promising therapeutic target for metabolic diseases. Glycine-ß-muricholic acid (Gly-MCA) is an intestine-specific FXR antagonist previously shown to have favorable metabolic effects on obesity and insulin resistance. Herein, we identify a role for Gly-MCA in the pathogenesis of NASH, and explore the underlying molecular mechanism. Gly-MCA improved lipid accumulation, inflammatory response, and collagen deposition in two different NASH models. Mechanistically, Gly-MCA decreased intestine-derived ceramides by suppressing ceramide synthesis-related genes via decreasing intestinal FXR signaling, leading to lower liver endoplasmic reticulum (ER) stress and proinflammatory cytokine production. The role of bile acid metabolism and adiposity was excluded in the suppression of NASH by Gly-MCA, and a correlation was found between intestine-derived ceramides and NASH severity. This study revealed that Gly-MCA, an intestine-specific FXR antagonist, has beneficial effects on NASH by reducing ceramide levels circulating to liver via lowering intestinal FXR signaling, and ceramide production, followed by decreased liver ER stress and NASH progression. Intestinal FXR is a promising drug target and Gly-MCA a novel agent for the prevention and treatment of NASH.

Bile acid and receptors: biology and drug discovery for nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD), a series of liver metabolic disorders manifested by lipid accumulation within hepatocytes, has become the primary cause of chronic liver diseases worldwide. About 20%-30% of NAFLD patients advance to nonalcoholic steatohepatitis (NASH), along with cell death, inflammation response and fibrogenesis. The pathogenesis of NASH is complex and its development is strongly related to multiple metabolic disorders (e.g. obesity, type 2 diabetes and cardiovascular diseases). The clinical outcomes include liver failure and hepatocellular cancer. There is no FDA-approved NASH drug so far, and thus effective therapeutics are urgently needed. Bile acids are synthesized in hepatocytes, transported into the intestine, metabolized by gut bacteria and recirculated back to the liver by the enterohepatic system. They exert pleiotropic roles in the absorption of fats and regulation of metabolism. Studies on the relevance of bile acid disturbance with NASH render it as an etiological factor in NASH pathogenesis. Recent findings on the functional identification of bile acid receptors have led to a further understanding of the pathophysiology of NASH such as metabolic dysregulation and inflammation, and bile acid receptors are recognized as attractive targets for NASH treatment. In this review, we summarize the current knowledge on the role of bile acids and the receptors in the development of NAFLD and NASH, especially the functions of farnesoid X receptor (FXR) in different tissues including liver and intestine. The progress in the development of bile acid and its receptors-based drugs for the treatment of NASH including bile acid analogs and non-bile acid modulators on bile acid metabolism is also discussed.