Interleukin 38 improves insulin resistance in hyperlipidemic skeletal muscle cells via PPARδ/SIRT1-mediated suppression of STAT3 signaling and oxidative stress.

The cytokine interleukin-38 (IL-38), a recently discovered member of the IL-1 family, has been shown to regulate inflammation and improve hepatic endoplasmic reticulum stress and lipid metabolism in individuals with obesity. However, its impact on insulin signaling in skeletal muscle cells and the underlying mechanisms remain unclear. In vitro obesity models were established using palmitate treatment, and Western blot analysis was performed to assess target proteins. Commercial kits were used to measure glucose uptake in cultured myocytes. Our study showed that IL-38 treatment alleviated the impairment of insulin signaling, including IRS-1 and Akt phosphorylation, and increased glucose uptake in palmitate-treated C2C12 myocytes. Increased levels of STAT3-mediated signaling and oxidative stress were observed in these cells following palmitate treatment, and these effects were reversed by IL-38 treatment. In addition, IL-38 treatment upregulated the expression of PPARδ, SIRT1 and antioxidants. Knockdown of PPARδ or SIRT1 using appropriate siRNAs abrogated the effects of IL-38 on insulin signaling, oxidative stress, and the STAT3-dependent pathway. These results suggest that IL-38 alleviates insulin resistance by inhibiting STAT3-mediated signaling and oxidative stress in skeletal muscle cells through PPARδ/SIRT1. This study provides fundamental evidence to support the potential use of IL-38 as a safe therapeutic agent for the treatment of insulin resistance and type 2 diabetes.

AMPK/autophagy-mediated alleviation of tendinopathy by IL-38: A novel strategy for the treatment of obesity-related tendinopathy.

The effect of interleukin-38 (IL-38), a recently identified member of the IL-1 family with potential applications in various inflammation-related conditions, on ER stress has not been explored. Furthermore, its role in obesity-associated tendinopathy has not been investigated. In this study, human primary tenocytes were treated with palmitate (200 or 400 µM) and palmitate plus IL-38 (0-50 ng/mL) for 24 h. Western blotting was used to assess ER stress and tendinopathogenic markers in tenocytes. Monodansylcadaverine (MDC) staining was used to evaluate autophagosomes. Apoptosis was determined by cell viability assays, caspase 3 activity assays and TUNEL assays. Cell migration was evaluated by a cell scratch assay. Small interfering (si) RNA transfection was used for target gene silencing. Treatment of tenocytes with IL-38 attenuated apoptosis, restored the balance between MMPs and TIMP-1, and alleviated ER stress under palmitate conditions. IL-38 treatment enhanced AMPK phosphorylation and promoted the expression of autophagy markers related to LC3 conversion, p62 degradation, and autophagosome formation in cultured tenocytes. The effects of IL-38 on ER stress, apoptosis, and MMP-9, MMP-13, and TIMP-1 expression in palmitate-treated tenocytes were abrogated by AMPK siRNA or 3-methyladenine (3MA). These results suggest that IL-38 alleviates ER stress through the AMPK/autophagy pathway, thereby reducing apoptosis and preventing extracellular matrix (ECM) degradation in tenocytes under hyperlipidemic conditions. This study provides a promising therapeutic avenue for treating obesity-related tendinopathy using an endogenous compound such as IL-38.

Aster glehni Extract, Including Caffeoylquinic Acids as the Main Constituents, Induces PPAR ß/δ-Dependent Muscle-Type Change and Myogenesis in Apolipoprotein E Knockout Mice.

To probe the functions of Aster glehni (AG) extract containing various caffeoylquinic acids on dyslipidemia, obesity, and skeletal muscle-related diseases focused on the roles of skeletal muscle, we measured the levels of biomarkers involved in oxidative phosphorylation and type change of skeletal muscle in C2C12 cells and skeletal muscle tissues from apolipoprotein E knockout (ApoE KO) mice. After AG extract treatment in cell and animal experiments, western blotting, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA) were used to estimate the levels of proteins that participated in skeletal muscle type change and oxidative phosphorylation. AG extract elevated protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), phosphorylated 5'-AMP-activated protein kinase (p-AMPK), peroxisome proliferator-activated receptor beta/delta (PPARß/δ), myoblast determination protein 1 (MyoD), and myoglobin in skeletal muscle tissues. Furthermore, it elevated the ATP concentration. However, protein expression of myostatin was decreased by AG treatment. In C2C12 cells, increments of MyoD, myoglobin, myosin, ATP-producing pathway, and differentiation degree by AG were dependent on PPARß/δ and caffeoylquinic acids. AG extract can contribute to the amelioration of skeletal muscle inactivity and sarcopenia through myogenesis in skeletal muscle tissues from ApoE KO mice, and function of AG extract may be dependent on PPARß/δ, and the main functional constituents of AG are trans-5-O-caffeoylquinic acid and 3,5-O-dicaffeoylquinic acid. In addition, in skeletal muscle, AG has potent efficacies against dyslipidemia and obesity through the increase of the type 1 muscle fiber content to produce more ATP by oxidative phosphorylation in skeletal muscle tissues from ApoE KO mice.

Madecassoside modulates lipid metabolism in visceral adipocytes: exploring the browning, lipolysis, and lipogenesis mechanisms for potential obesity treatment.

OBJECTIVES: Madecassoside (MA) is a triterpene derived from Centella asiatica that has been recognized for its antioxidant and anti-inflammatory properties in various disease models. However, its direct impact on cultured white adipocytes and the underlying mechanisms, mainly through gene knockdown, have not been thoroughly explored. METHODS: Western blot analysis was utilized to assess the expression levels of various proteins, while oil red O staining was used to measure lipid deposition. The adipocyte shapes were confirmed using H&E staining. KEY FINDINGS: MA treatment enhanced browning and lipolysis in 3T3-L1 adipocytes and adipose tissue from experimental mice while suppressing lipogenesis. Furthermore, MA treatment increased the expression of PPARα and FGF21 in 3T3-L1 adipocytes as well as the secretion of FGF21 into the culture medium. Knockdown of PPARα or FGF21 using siRNA diminished the effects of MA on lipid metabolism in cultured adipocytes. CONCLUSIONS: These findings demonstrate that MA promotes thermogenic browning and lipolysis while inhibiting adipocyte lipogenesis, thus showing the potential for attenuating obesity. The study suggested that MA could be a viable therapeutic approach for treating obesity.

Interleukin-27 as a novel player in alleviating hepatic steatosis: Mechanistic insights from an in vitro analysis.

Interleukin-27 (IL-27) is a recently discovered cytokine that has been implicated in inflammatory and metabolic conditions, such as atherosclerosis and insulin resistance. However, the mechanisms by which IL-27 attenuates hepatic lipid accumulation in hyperlipidemic conditions and counteracts endoplasmic reticulum (ER) stress, a known risk factor for impaired hepatic lipid metabolism, have not been elucidated. This in vitro study was designed to examine the effect of IL-27 on hepatic lipid metabolism. The study included the evaluation of lipogenesis-associated proteins and ER stress markers by Western blotting, the determination of hepatic lipid accumulation by Oil Red O staining, and the examination of autophagosome formation by MDC staining. The results showed that IL-27 treatment reduced lipogenic lipid deposition and the expression of ER stress markers in cultured hepatocytes exposed to palmitate. Moreover, treatment with IL-27 suppressed CD36 expression and enhanced fatty acid oxidation in palmitate-treated hepatocytes. The effects of IL-27 on hyperlipidemic hepatocytes were attenuated when adenosine monophosphate-activated protein kinase (AMPK) or 3-methyladenine (3 MA) were inhibited by small interfering RNA (siRNA). These results suggest that IL-27 attenuates hepatic ER stress and fatty acid uptake and stimulates fatty acid oxidation via AMPK/autophagy signaling, thereby alleviating hepatic steatosis. In conclusion, this study identified IL-27 as a promising therapeutic target for nonalcoholic fatty liver disease (NAFLD).

DEL-1: a promising treatment for AMD-associated ER stress in retinal pigment epithelial cells.

BACKGROUND: Age-related macular degeneration (AMD) is an irreversible eye disease that can cause blurred vision. Regular exercise has been suggested as a therapeutic strategy for treating AMD, but how exercise improves AMD is not yet understood. This study investigated the protective effects of developmental endothelial locus-1 (DEL-1), a myokine upregulated during exercise, on endoplasmic reticulum (ER) stress-induced injury in retinal pigment epithelial cells. METHODS: We evaluated the levels of AMPK phosphorylation, autophagy markers, and ER stress markers in DEL-1-treated human retinal pigment epithelial cells (hRPE) using Western blotting. We also performed cell viability, caspase 3 activity assays, and autophagosome staining. RESULTS: Our findings showed that treatment with recombinant DEL-1 dose-dependently reduced the impairment of cell viability and caspase 3 activity in tunicamycin-treated hRPE cells. DEL-1 treatment also alleviated tunicamycin-induced ER stress markers and VEGF expression. Moreover, AMPK phosphorylation and autophagy markers were increased in hRPE cells in the presence of DEL-1. However, the effects of DEL-1 on ER stress, VEGF expression, and apoptosis in tunicamycin-treated hRPE cells were reduced by AMPK siRNA or 3-methyladenine (3-MA), an autophagy inhibitor. CONCLUSIONS: Our study suggests that DEL-1, a myokine, may have potential as a treatment strategy for AMD by attenuating ER stress-induced injury in retinal pigment epithelial cells.

Interleukin-38 alleviates hepatic steatosis through AMPK/autophagy-mediated suppression of endoplasmic reticulum stress in obesity models.

Interleukin-38 (IL-38), recently recognized as a cytokine with anti-inflammatory properties that mitigate type 2 diabetes, has been associated with indicators of insulin resistance and nonalcoholic fatty liver disease (NAFLD). This study investigated the impact of IL-38 on hepatic lipid metabolism and endoplasmic reticulum (ER) stress. We assessed protein expression levels using Western blot analysis, while monodansylcadaverine staining was employed to detect autophagosomes in hepatocytes. Oil red O staining was utilized to examine lipid deposition. The study revealed elevated serum IL-38 levels in high-fat diet (HFD)-fed mice and IL-38 secretion from mouse keratinocytes. IL-38 treatment attenuated lipogenic lipid accumulation and ER stress markers in hepatocytes exposed to palmitate. Furthermore, IL-38 treatment increased AMP-activated protein kinase (AMPK) phosphorylation and autophagy. The effects of IL-38 on lipogenic lipid deposition and ER stress were nullified in cultured hepatocytes by suppressing AMPK through small interfering (si) RNA or 3-methyladenine (3MA). In animal studies, IL-38 administration mitigated hepatic steatosis by suppressing the expression of lipogenic proteins and ER stress markers while reversing AMPK phosphorylation and autophagy markers in the livers of HFD-fed mice. Additionally, AMPK siRNA, but not 3MA, mitigated IL-38-enhanced fatty acid oxidation in hepatocytes. In summary, IL-38 alleviates hepatic steatosis through AMPK/autophagy signaling-dependent attenuation of ER stress and enhancement of fatty acid oxidation via the AMPK pathway, suggesting a therapeutic strategy for treating NAFLD.

CTRP4 ameliorates inflammation, thereby attenuating the interaction between HUVECs and THP-1 monocytes through SIRT6/Nrf2 signaling.

CTRP4, identified as an adipokine, has demonstrated notable anti-inflammatory and anti-obesity effects in various disease models. Consequently, our research sought to explore the impact of CTRP4 on inflammation and the interaction between endothelial cells and monocytes in hyperlipidemic conditions. Using Western blotting, we assessed the expression levels of various proteins in HUVECs and THP-1 monocytes. Our study findings indicate that treatment with CTRP4 effectively mitigated the attachment of THP-1 monocytes to HUVECs. Furthermore, it reduced the expression of adhesion molecules and inflammation indicators in experimental cells exposed to hyperlipidemic conditions. Notably, CTRP4 treatment led to an increase in SIRT6 expression and the nuclear translocation of Nrf2. Interestingly, when SIRT6 or Nrf2 was silenced using siRNA, the positive effects of CTRP4 in HUVECs and THP-1 cells were nullified. Our results suggest that CTRP4 exhibits anti-inflammatory properties, thereby improving the interaction between endothelial cells and monocytes through the SIRT6/Nrf2-dependent pathway. This study provides insights into CTRP4 as a potential therapeutic target for mitigating obesity-related atherosclerosis.

Musclin Mitigates the Attachment of HUVECs to THP-1 Monocytes in Hyperlipidemic Conditions through PPARα/HO-1-Mediated Attenuation of Inflammation.

Musclin, a myokine, undergoes modulation during exercise and has demonstrated anti-inflammatory effects in cardiomyocytes and glomeruli. However, its role in atherosclerotic responses remains unclear. This study aimed to explore the impact of musclin on inflammatory responses and the interaction between endothelial cells and monocytes under hyperlipidemic conditions. The attachment levels of THP-1 monocytes on cultured HUVECs were examined. Inflammation and the expression of cell adhesion molecules were also evaluated. To explore the molecular mechanisms of musclin, PPARα or heme oxygenase 1 (HO-1) siRNA transfection was performed in HUVECs. The results revealed that treatment with recombinant musclin effectively suppressed the attachment of palmitate-induced HUVECs to THP-1 cells and reduced the expression of cell adhesion proteins (ICAM-1, VCAM-1, and E-selectin) in HUVECs. Furthermore, musclin treatment ameliorated the expression of inflammation markers (phosphorylated NFκB and IκB) in both HUVECs and THP-1 monocytes, as well as the release of TNFα and MCP-1 from HUVECs and THP-1 monocytes. Notably, musclin treatment augmented the expression levels of PPARα and HO-1. However, when PPARα or HO-1 siRNA was employed, the beneficial effects of musclin on inflammation, cell attachment, and adhesion molecule expression were abolished. These findings indicate that musclin exerts anti-inflammatory effects via the PPARα/HO-1 pathway, thereby mitigating the interaction between endothelial cells and monocytes. This study provides evidence supporting the important role of musclin in ameliorating obesity-related arteriosclerosis and highlights its potential as a therapeutic agent for treating arteriosclerosis.

Therapeutic potential of ginsenoside compound K in managing tenocyte apoptosis and extracellular matrix damage in diabetic tendinopathy.

The prevalence of tendinopathy in patients with diabetes is well documented. Despite efforts to improve diabetes management, there is a lack of research on therapeutic agents targeting the core features of tendinopathy, namely, tenocyte apoptosis and extracellular matrix (ECM) damage. In this study, we investigated the potential of ginsenoside compound K (CK), known for its antidiabetic properties, to mitigate tenocyte apoptosis, inflammation, oxidative stress, and the metalloproteinase (MMP) system under hyperglycemic conditions. Our research also aimed to unravel the molecular mechanism underlying the effects of CK. The assessment of apoptosis involved observing intracellular chromatin condensation and measuring caspase 3 activity. To gauge oxidative stress, we examined cellular ROS levels and hydrogen peroxide and malondialdehyde concentrations. Western blotting was employed to determine the expression of various proteins. Our findings indicate that CK treatment effectively countered high glucose-induced apoptosis, inflammation, and oxidative stress in cultured tenocytes. Furthermore, CK normalized the expression of MMP-9, MMP-13, and TIMP-1. Notably, CK treatment boosted the expression of PPARγ and antioxidant enzymes. We conducted small interfering (si) RNA experiments targeting PPARγ, revealing its role in mediating CK's effects on tendinopathy features in hyperglycemic tenocytes. In conclusion, these in vitro results offer valuable insights into the potential therapeutic role of CK in managing tendinopathy among individuals with diabetes. By addressing crucial aspects of tendinopathy, CK presents itself as a promising avenue for future research and treatment development in this domain.

IL-38 alleviates atherogenic responses via SIRT6/HO-1 signaling: A promising strategy against obesity-related atherosclerosis.

Interleukin-38 (IL-38), a member of the IL-1 family, is known for its anti-inflammatory properties mediated through ligand signaling in various disease models. It plays a significant role in atherosclerosis development, forming a theoretical basis for therapeutic strategies. However, the direct effects of IL-38 on atherogenic responses in the vascular endothelium and monocytes remain unclear. In this investigation, IL-38 treatment reduced THP-1 monocyte adhesion to HUVECs, decreased the expression of vascular adhesion molecules, and mitigated inflammation in the presence of palmitate. IL-38 treatment upregulated SIRT6 expression and enhanced autophagy markers such as LC3 conversion and p62 degradation. The effects of IL-38 were nullified by siRNA-mediated suppression of SIRT6 or heme oxygenase-1 (HO-1) in HUVECs and palmitate-treated THP-1 cells. These findings reveal that IL-38 mitigates inflammation through the SIRT6/HO-1 pathway, offering a potential therapeutic approach for addressing obesity-related atherosclerosis.

CTRP4 attenuates apoptosis and epithelial-mesenchymal transition markers in podocytes through an AMPK/autophagy-dependent pathway.

Hyperglycemia, characterized by high blood glucose levels resulting from pancreatic beta cell dysfunction or impaired insulin signaling, is a contributing factor in the development of diabetic nephropathy. This study aimed to investigate the effects of C1q/TNF-related protein 4 (CTRP4), known for its anti-obesity and anti-inflammatory properties in various disease models, on podocyte apoptosis and endoplasmic reticulum (ER) stress in the presence of elevated glucose levels. The expression levels of various proteins in podocytes and adipocytes were evaluated by Western blotting. Autophagosomes in podocytes were stained by MDC. Chromatin condensation in podocytes was examined by Hoechst staining. The research revealed increased expression of CTRP4 in 3T3-L1 adipocytes and CIHP-1 podocytes exposed to high glucose (HG) conditions. Treatment with CTRP4 effectively mitigated HG-induced apoptosis and ER stress and normalized epithelial-to-mesenchymal transition (EMT) markers in CIHP-1 cells. Furthermore, elevated levels of AMPK phosphorylation and autophagy were observed in CIHP-1 cells treated with CTRP4. Silencing of AMPK or the use of 3-methyl adenine (3 MA) reduced the impacts of CTRP4 on apoptosis, EMT markers and ER stress in CIHP-1 cells. In conclusion, these findings suggest that CTRP4 alleviates ER stress in podocytes under hyperglycemic conditions, leading to the suppression of apoptosis and the restoration of EMT through AMPK/autophagy-mediated signaling. These insights provide valuable information for the development of therapeutic strategies for diabetic nephropathy.

Madecassoside ameliorates hepatic steatosis in high-fat diet-fed mice through AMPK/autophagy-mediated suppression of ER stress.

Hepatic endoplasmic reticulum (ER) stress is a contributing factor in the development of hepatic steatosis in obesity. Madecassoside (MA), a pentacyclic triterpene derived from Centella asiatica, is known for its anti-inflammatory properties in the treatment of skin wounds. However, the impact of MA on hepatic ER stress and lipid metabolism in experimental obesity models has not been investigated. In this study, we examined the effects of MA on primary hepatocytes treated with palmitate and the livers of mice fed a high-fat diet (HFD). Our findings demonstrated that MA treatment reduced lipogenic lipid accumulation, apoptosis, and ER stress in hepatocytes. Additionally, MA treatment increased the phosphorylation of AMP-activated protein kinase (AMPK) and markers of autophagy. Importantly, when AMPK was inhibited by small interfering RNA (siRNA) or autophagy was blocked by 3-methyladenine (3MA), the protective effects of MA against ER stress, lipogenic lipid deposition, and apoptosis in palmitate-treated hepatocytes were abolished. These results suggest that MA mitigates hepatic steatosis in obesity through an AMPK/autophagy-dependent pathway. The present study highlights the potential of MA as a promising therapeutic candidate for hepatic steatosis.

Buspirone Induces Weight Loss and Normalization of Blood Pressure via the Stimulation of PPARδ Dependent Energy Producing Pathway in Spontaneously Hypertensive Rats.

Introduction: Buspirone, as a partial agonist for a 5-hydroxytryptamine (serotonin) receptor 1A (5-HT1A), has been prescribed as an anxiolytic drug for patients. In addition, the lowering effect of serotonin on blood pressure was reported in hypertensive animal model. We investigated the therapeutic mechanism of buspirone against lipid metabolism disturbed by hypertension of early stage via hypertensive and obese animal model. Methods: The levels of various biomarkers related to lipid metabolism and hypertension were estimated through the measurement of body weight and fat weight, blood analysis, western blotting, immunohistochemistry, and staining methods. Results: The lipid accumulation was lowered in differentiated 3T3-L1 cells by buspirone treatments of 50 and 100 µM compared with untreated differentiated control. Body weight and abdominal fat weight were lowered in spontaneously hypertensive rats (SHRs) administered with buspirone of 10 mg/kg/day for 4 weeks than 8-week untreated group. Triglyceride (TG) level was decreased in SHRs administered with buspirone of 5 and 10 mg/kg/day compared to 8-week untreated group. High-density lipoprotein (HDL)-cholesterol concentration was elevated by buspirone 10 mg/kg/day treatment compared to 8-week untreated group. Blood pressures in SHRs were lowered by buspirone treatments of 5 and 10 mg/kg/day compared with 8-week untreated group. Protein levels for peroxisome proliferator-activated receptor δ (PPARδ), 5' adenosine monophosphate-activated protein kinase (AMPK), and PPARγ coactivator-1 alpha (PGC-1α) were increased both in C2C12 cells treated by buspirone of 100 µM and in SHRs administered by buspirone of 1, 5, and 10 mg/kg/day compared to untreated control cells and 8-week untreated group. Fat cell numbers decreased in 8-week untreated group were increased in SHRs administered by buspirone treats of 1, 5, and 10 mg/kg/day. Protein expression levels for angiotensin II type 1 receptor (AT1R) and vascular cell adhesion molecule 1 (VCAM1) were increased in 8-week untreated group compared to 4-week group, however, they were decreased by buspirone treatments of 1, 5, and 10 mg/kg/day. Conclusion: Buspirone may induce the losses of body weight and abdominal fat weight through the activation of PPARδ dependent catabolic metabolism producing energy, and eventually, the ameliorated lipid metabolism could normalize high blood pressure.

Ginsenoside Rb3 ameliorates podocyte injury under hyperlipidemic conditions via PPARδ- or SIRT6-mediated suppression of inflammation and oxidative stress.

Background: Rb3 is a ginsenoside with anti-inflammatory properties in many cell types and has been reported to attenuate inflammation-related metabolic diseases such as insulin resistance, nonalcoholic fatty liver disease, and cardiovascular disease. However, the effect of Rb3 on podocyte apoptosis under hyperlipidemic conditions, which contributes to the development of obesity-mediated renal disease, remains unclear. In the current study, we aimed to investigate the effect of Rb3 on podocyte apoptosis in the presence of palmitate and explore its underlying molecular mechanisms. Methods: Human podocytes (CIHP-1 cells) were exposed to Rb3 in the presence of palmitate as a model of hyperlipidemia. Cell viability was assessed by MTT assay. The effects of Rb3 on the expression of various proteins were analyzed by Western blotting. Apoptosis levels were determined by MTT assay, caspase 3 activity assay, and cleaved caspase 3 expression. Results: We found that Rb3 treatment alleviated the impairment of cell viability and increased caspase 3 activity as well as inflammatory markers in palmitate-treated podocytes. Treatment with Rb3 dose-dependently increased PPARδ and SIRT6 expression. Knockdown of PPARδ or SIRT6 reduced the effects of Rb3 on apoptosis as well as inflammation and oxidative stress in cultured podocytes. Conclusions: The current results suggest that Rb3 alleviates inflammation and oxidative stress via PPARδ- or SIRT6-mediated signaling, thereby attenuating apoptosis in podocytes in the presence of palmitate. The present study provides Rb3 as an effective strategy for treating obesity-mediated renal injury.

Musclin attenuates lipid deposition in hepatocytes through SIRT7/autophagy-mediated suppression of ER stress.

Musclin, an exercise-responsive myokine, has the ability to attenuate inflammation, oxidative stress, and apoptosis in cardiomyocytes under pathogenic conditions. While the potential benefits of musclin in the cardiovascular system have been well documented, its effects on hepatic endoplasmic reticulum (ER) stress and lipid metabolism are not fully understood. The present study showed that musclin treatment reduced lipid accumulation and lipogenic protein expression in primary hepatocytes exposed to palmitate. Palmitate treatment led to an increase in markers of ER stress, which was reversed by musclin treatment. Musclin treatment increased SIRT7 expression and markers of autophagy in a dose-dependent manner. Small interfering (si) RNA of SIRT7 or 3-methyladenine (3 MA) reduced the effects of musclin on lipogenic lipid deposition in hepatocytes under hyperlipidemic conditions. These findings suggest that musclin can suppress palmitate-induced ER stress by upregulating SIRT7 and autophagy signaling, thereby alleviating lipid accumulation in primary hepatocytes. The current study provides a potential therapeutic strategy for the treatment of liver diseases characterized by lipid accumulation and ER stress, such as nonalcoholic fatty liver disease (NAFLD).

Adipokine gremlin-1 promotes hepatic steatosis via upregulation of ER stress by suppressing autophagy-mediated signaling.

Gremlin-1 (GR1) is a novel adipokine that is highly expressed in human adipocytes and has been shown to inhibit the BMP2/4-TGFb signaling pathway. It has an effect on insulin sensitivity. Elevated levels of Gremlin have been shown to lead to insulin resistance in skeletal muscle, adipocytes, and hepatocytes. In this study, we investigated the effect of GR1 on hepatic lipid metabolism under hyperlipidemic conditions and explored the molecular mechanisms associated with GR1 by in vitro and in vivo studies. We found that palmitate increased GR1 expression in visceral adipocytes. Recombinant GR1 increased lipid accumulation, lipogenesis, and ER stress markers in cultured primary hepatocytes. Treatment with GR1 increased EGFR expression and mTOR phosphorylation and reduced autophagy markers. EGFR or rapamycin siRNA reduced the effects of GR1 on lipogenic lipid deposition and ER stress in cultured hepatocytes. Administration of GR1 via the tail vein induced lipogenic proteins and ER stress while suppressing autophagy in the livers of experimental mice. Suppression of GR1 by in vivo transfection reduced the effects of a high-fat diet on hepatic lipid metabolism, ER stress, and autophagy in mice. These results suggest that the adipokine GR1 promotes hepatic ER stress due to the impairment of autophagy, ultimately causing hepatic steatosis in the obese state. The current study demonstrated that targeting GR1 may be a potential therapeutic approach for treating metabolic diseases, including metabolic-associated fatty liver disease (MAFLD).

Oroxylin-A alleviates hepatic lipid accumulation and apoptosis under hyperlipidemic conditions via AMPK/FGF21 signaling.

Oroxylin-A (OA) is an O-methylated flavone that has been demonstrated to have anti-inflammatory properties in various disease models. However, the roles of OA in hepatic lipid metabolism and the specific molecular mechanisms by which it exerts these effects are not yet fully understood. In the current study, we aimed to investigate the effects of OA on hepatic lipid deposition and apoptosis, which play a pivotal role in the development of nonalcoholic fatty liver disease (NAFLD) in obesity in vitro models. We found that treatment with OA attenuated lipid accumulation, the expression of lipogenesis-associated proteins and apoptosis in palmitate-treated primary mouse hepatocytes. OA treatment suppressed phosphorylated NFκB and IκB expression in as well as TNFα and MCP-1 release from hepatocytes treated with palmitate. Treatment of hepatocytes with OA augmented AMPK phosphorylation and FGF21 expression. siRNA of AMPK or FGF21 abolished the effects of OA on inflammation as well as lipid accumulation and apoptosis in hepatocytes under palmitate treatment conditions. In conclusion, OA improves inflammation through the AMPK/FGF21 pathway, thereby attenuating lipid accumulation and apoptosis in hepatocytes. This study may help identify new targets for developing treatments for NAFLD.

Humulus japonicus Extract Ameliorates Hepatic Steatosis Through the PPARα-Mediated Suppression of Alcohol-Induced Oxidative Stress.

Humulus japonicus has been used to treat obesity, hypertension, and nonalcoholic fatty liver and to alleviate inflammation and oxidative stress. In the present study, we aimed to investigate the effects of H. japonicus ethanol extracts (HE) and luteolin 7-O-ß-d-glucoside (LU), which is identified as a major active component of H. japonicus, on ethanol-induced oxidative stress and lipid accumulation in primary hepatocytes. Mouse primary hepatocytes were treated with HE and stimulated with ethanol. The MTT test was used to determine cell viability. By using Western blotting, the effects of HE on the expression of different proteins were investigated. Experimental mice were given a 5% alcohol liquid Lieber-DeCarli diet to induce alcoholic fatty liver. We found that both HE and LU individually attenuated ethanol-induced lipid accumulation, lipogenic protein expression, and cellular oxidative stress in hepatocytes. Treatment with HE or LU increased PPARα and SOD1 expression and catalase activity in a dose-dependent manner. Small interfering RNA of PPARα reduced the effects of HE on oxidative stress, lipid metabolism, and levels of antioxidants. We also observed that orally administered HE treatment alleviated hepatic steatosis in a diet containing ethanol-fed mice. This study suggests HE as a functional food that can improve hepatic steatosis, thereby preventing hepatic injury caused by alcohol consumption.

Corrigendum to "Ginsenoside compound K ameliorates palmitate-induced atrophy in C2C12 myotubes via promyogenic effects and AMPK/autophagy-mediated suppression of endoplasmic reticulum stress" [J Ginseng Res 46(3) May 2022 444-453].

[This corrects the article DOI: 10.1016/j.jgr.2021.09.002.].