CD9 Counteracts Liver Steatosis and Mediates GCGR Agonist Hepatic Effects.

Glucagon receptor (GCGR) agonism offers potentially greater effects on the mitigation of hepatic steatosis. However, its underlying mechanism is not fully understood. Here, it screened tetraspanin CD9 might medicate hepatic effects of GCGR agonist. CD9 is decreased in the fatty livers of patients and upregulated upon GCGR activation. Deficiency of CD9 in the liver exacerbated diet-induced hepatic steatosis via complement factor D (CFD) regulated fatty acid metabolism. Specifically, CD9 modulated hepatic fatty acid synthesis and oxidation genes through regulating CFD expression via the ubiquitination-proteasomal degradation of FLI1. In addition, CD9 influenced body weight by modulating lipogenesis and thermogenesis of adipose tissue through CFD. Moreover, CD9 reinforcement in the liver alleviated hepatic steatosis, and blockage of CD9 abolished the remission of hepatic steatosis induced by cotadutide treatment. Thus, CD9 medicates the hepatic beneficial effects of GCGR signaling, and may server as a promising therapeutic target for hepatic steatosis.

PSA controls hepatic lipid metabolism by regulating the NRF2 signaling pathway.

The activity of proteinase is reported to correlate with the development and progression of nonalcoholic fatty liver disease (NAFLD). Puromycin-sensitive aminopeptidase (PSA/NPEPPS) is an integral nontransmembrane enzyme that functions to catalyze the cleavage of amino acids near the N-terminus of polypeptides. A previous study suggested that this enzyme acts as a regulator of neuropeptide activity; however, the metabolic function of this enzyme in the liver has not been explored. Here, we identified the novel role of PSA in hepatic lipid metabolism. Specifically, PSA expression was lower in fatty livers from NAFLD patients and mice (HFD, ob/ob, and db/db). PSA knockdown in cultured hepatocytes exacerbated diet-induced triglyceride accumulation through enhanced lipogenesis and attenuated fatty acid ß-oxidation. Moreover, PSA mediated activation of the master regulator of antioxidant response, nuclear factor erythroid 2-related factor 2 (NRF2), by stabilizing NRF2 protein expression, which further induced downstream antioxidant enzymes to protect the liver from oxidative stress and lipid overload. Accordingly, liver-specific PSA overexpression attenuated hepatic lipid accumulation and steatosis in ob/ob mice. Furthermore, in human liver tissue samples, decreased PSA expression correlated with the progression of NAFLD. Overall, our findings suggest that PSA is a pivotal regulator of hepatic lipid metabolism and its antioxidant function occurs by suppressing NRF2 ubiquitination. Moreover, PSA may be a potential biomarker and therapeutic target for treating NAFLD.

Deficiency of Mitochondrial Glycerol 3-Phosphate Dehydrogenase Exacerbates Podocyte Injury and the Progression of Diabetic Kidney Disease.

Mitochondrial function is essential for bioenergetics, metabolism, and signaling and is compromised in diseases such as proteinuric kidney diseases, contributing to the global burden of kidney failure, cardiovascular morbidity, and death. The key cell type that prevents proteinuria is the terminally differentiated glomerular podocyte. In this study, we characterized the importance of mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH), located on the inner mitochondrial membrane, in regulating podocyte function and glomerular disease. Specifically, podocyte-dominated mGPDH expression was downregulated in the glomeruli of patients and mice with diabetic kidney disease and adriamycin nephropathy. Podocyte-specific depletion of mGPDH in mice exacerbated diabetes- or adriamycin-induced proteinuria, podocyte injury, and glomerular pathology. RNA sequencing revealed that mGPDH regulated the receptor for the advanced glycation end product (RAGE) signaling pathway, and inhibition of RAGE or its ligand, S100A10, protected against the impaired mitochondrial bioenergetics and increased reactive oxygen species generation caused by mGPDH knockdown in cultured podocytes. Moreover, RAGE deletion in podocytes attenuated nephropathy progression in mGPDH-deficient diabetic mice. Rescue of podocyte mGPDH expression in mice with established glomerular injury significantly improved their renal function. In summary, our study proposes that activation of mGPDH induces mitochondrial biogenesis and reinforces mitochondrial function, which may provide a potential therapeutic target for preventing podocyte injury and proteinuria in diabetic kidney disease.

Dedicator of Cytokinesis 5 Regulates Keratinocyte Function and Promotes Diabetic Wound Healing.

Cutaneous wound healing is a fundamental biologic and coordinated process, and failure to maintain this process contributes to the dysfunction of tissue homeostasis, increasing the global burden of diabetic foot ulcerations. However, the factors that mediate this process are not fully understood. Here, we identify the pivotal role of dedicator of cytokinesis 5 (Dock5) in keratinocyte functions contributing to the process of skin wound healing. Specifically, Dock5 is highly upregulated during the proliferative phase of wound repair and is predominantly expressed in epidermal keratinocytes. It regulates keratinocyte adhesion, migration, and proliferation and influences the functions of extracellular matrix (ECM) deposition by facilitating the ubiquitination of transcription factor ZEB1 to activate laminin-332/integrin signaling. Genetic ablation of Dock5 in mice leads to attenuated reepithelialization and granulation tissue formation, and Dock5 overexpression-improved skin repair can be abrogated by LAMA3 knockdown. Importantly, Dock5 expression in the skin edge is reduced in patients and animal models of diabetes, further suggesting a direct correlation between its abundance and healing capability. The rescue of Dock5 expression in diabetic mice causes a significant improvement in reepithelialization, collagen deposition, ECM production, and granulation. Our study provides a potential therapeutic target for wound healing impairment during diabetes.

Decreased Plasma Maresin 1 Concentration Is Associated with Diabetic Foot Ulcer.

AIMS: To assess the maresin 1 (MaR1) contents in type 2 diabetic patients with or without diabetic foot ulcer and to analyze the association of MaR1 concentrations with several metabolism-related parameters. METHODS: Plasma MaR1 concentrations were analyzed in 96 subjects with normal glucose tolerant (NC, n = 43), type 2 diabetes (T2DM, n = 40), or diabetic foot ulcer (DFU, n = 13). The intravenous glucose tolerance test (IVGTT) and biochemical parameters were measured in all participants. RESULTS: Plasma MaR1 concentrations were significant decreased in type 2 diabetes patient with or without DFU compared with NC (both P < 0.001) and were lowest in DFU patients among these 3 groups. (DFU vs. T2DM, P < 0.05). Plasma MaR1 concentrations were negatively correlated with BMI, waist circumference (Wc), waist hip ratio (WHR), systolic blood pressure (SBP), diastolic blood pressure (DBP), LDL-c, FPG, 2hPG, HbA1c, and homeostasis model assessment for insulin resistance (HOMA-IR) (all P < 0.05) and were positively correlated with HDL-c, acute insulin response (AIR), area under the curve of the first-phase (0-10 min) insulin secretion (AUC), and homeostasis model assessment for beta-cell function (HOMA-ß) (all P < 0.05). After adjusting for age and sex, Wc, WHR, TG, FPG, 2hPG, HbA1c, HOMA-IR, AIR, AUC, and HOMA-ß remain statistically significant (all P < 0.05). CONCLUSIONS: Plasma MaR1 concentration were decreased in T2DM with or without DFUs and were the lowest in DFU patients. The decreased plasma MaR1 strongly associated with obesity, impaired glucose and lipid metabolism, reduced first-phase of glucose-stimulated insulin secretion, and enhanced insulin resistance.