Ginsenoside Rb1 mitigates senescence-associated hepatic steatosis in mice through enhanced lysine degradation

The aim of this study is to investigate whether AMP-activated protein kinase α2 (AMPKα2) is essential for wolfberry's protective effects on mitochondrial dysfunction and subsequent hepatic steatosis in mice. Six-week-old male AMPKα2 knockout mice and genetic background C57BL/6J (B6) mice were fed a control, high-fat diet (HD, 45% (kilocalorie) fat), and/or HD with 5% (kilocalarie) wolfberry diets for 18 wk. At termination, blood and liver tissues were sampled for analysis by ELISA, HPLC, microscopy, real-time PCR, and Western blot. HD lowered hepatic lutein and zeaxanthin contents, inhibited protein expression of β,β-carotene 9',10'-oxygenase 2 (BCO2) and heat shock protein 60 in mitochondria, increased reactive oxygen species level, and suppressed mitophagy and mitochondrial biogenesis as determined by accumulation of p62, inhibited phosphorylation of Unc-51-like kinase 1 on Ser555, and declined expression of peroxisome proliferator-activated receptor γ coactivator 1 α, resulting in hepatic steatosis in B6 and knockout mice. Dietary wolfberry elevated the xanthophyll concentrations and enhanced expression of BCO2 and heat shock protein 60, attenuated mitochondrial oxidative stress, activated AMPKα2, potentiated mitophagy and mitochondrial biogenesis, and enhanced lipid oxidation and secretion in the liver of B6 mice. Dietary wolfberry selectively activated AMPKα2, which resulted in enhanced mitochondrial biogenesis and potentiated mitophagy, leading to the prevention of hepatic steatosis in obese mice.

Scope: Gut microbiome-derived metabolites are the major mediators of diet-induced host-microbial interactions. Aryl hydrocarbon receptor (AHR) plays a crucial role in glucose, lipid, and cholesterol metabolism in the liver. In this study, we aimed to investigate the role of indole-3-acetic acid (IAA) and AHR in sulforaphane (SFN) alleviates hepatic steatosis in mice fed on a high-fat diet (HFD).Methods and Results: The HFD-fed male C57BL/6 mice were intervened with SFN for 6 weeks. HFD-mice showed classical pathophysiological characteristics of hepatic steatosis. The results showed that SFN significantly reduced body weight, liver inflammation and hepatic steatosis in HFD-fed mice. SFN reduced hepatic lipogenesis by activating AHR/SREBP-1C pathway, which was confirmed in HepG2 cell experiments. Moreover, SFN increased hepatic antioxidant activity by modulating Nrf-2/NQO1 expression. SFN increased serum and liver IAA level in HFD mice. Notably, SFN manipulated the gut microbiota, resulting in reducing Deferribacteres and proportions of the phylum Firmicutes/Bacteroidetes and increasing the abundance of specific bacteria that produce IAA. Furthermore, SFN upregulated Ahr expression and decreased the expression of inflammatory cytokines in Raw264.7 cells.Conclusions: SFN ameliorated hepatic steatosis not only by modulating lipid metabolism via AHR/SREBP-1C pathway but regulating IAA and gut microbiota in HFD-induced NAFLD mice.

Chronic intake of trans‐10, cis‐12 conjugated linoleic acid (t10, c12 CLA) causes detrimental effects such as lipid accumulation in liver and increased expression of the pro‐inflammatory cytokine tumor necrosis factor alpha (TNFα) in adipose tissue depots. TNFα is involved in dysregulation of hepatic lipid metabolism and insulin signaling. The role of TNFα in mediating the stimulatory effects of t10, c12 CLA on lipid accumulation in liver is unclear. To examine this issue, wild type C57BL/6J female mice (WT) and their counterparts lacking both TNFα receptor‐1 and 2 (TNFRKO) were fed diets containing 0.5% of either oleic acid or t10, c12 CLA for 2 weeks. As expected, t10, c12 CLA reduced adipose tissue mass and caused hyperinsulinemia and hepatic steatosis in WT mice. Hepatic steatosis in WT mice was associated with increased expression of many enzymes involved in lipogenesis. Surprisingly, the effects of t10, c12 CLA in TNFRKO liver were maintained for lipogenic gene expression and exacerbated for steatosis. We conclude that the effects of t10, c12 CLA on hepatic lipid metabolism do not require TNFα signaling.

Corosolic acid (CRA), a constituent of Banaba leaves, has been reported to exert anti-hypertension, anti-hyperinsulinemia, anti-hyperglycemia, and anti-hyperlipidemia effects as well as to induce anti-inflammatory and anti-oxidative activities. The aim of this study was to investigate the inhibitory effects of CRA on the development of obesity and hepatic steatosis in KK-Ay mice, a genetically obese mouse model. Six-week-old KK-Ay mice were fed a high fat diet for 9 weeks with or without 0.023% CRA. Nine-week CRA treatment resulted in 10% lower body weight and 15% lower total fat (visceral plus subcutaneous fat) mass than in control mice. CRA treatment reduced fasting plasma levels of glucose, insulin, and triglyceride by 23%, 41%, and 22%, respectively. The improved insulin sensitivity in CRA-treated mice may be due on part to the increased plasma adiponectin and white adipose tissue (WAT) AdipoR1 levels. In addition, CRA treatment increased the expression of peroxisome proliferator-activated receptor (PPAR) alpha in liver and PPAR gamma in WAT. This is the first study to show that CRA treatment can contribute to reduced body weight and amelioration of hepatic steatosis in mice fed a high fat diet, due in part to increased expression of PPAR alpha in liver and PPAR gamma in WAT.

The visceral organ-brain axis, mediated by vagal sensory neurons, is essential for maintaining various physiological functions. Here, we investigate the impact of liver-projecting vagal sensory neurons on energy balance, hepatic steatosis, and anxiety-like behavior in mice under obesogenic conditions. A small subset of vagal sensory neurons in both the left and right ganglia innervate the liver and project centrally to the nucleus of the tractus solitarius, area postrema, and dorsal motor nucleus of the vagus, and peripherally to the periportal areas in the liver. Surprisingly, the loss of liver-projecting vagal sensory neurons via caspase-induced selective destruction of advillin-positive neurons prevents diet-induced obesity, and these outcomes are associated with increased energy expenditure. Although males and females exhibit improved glucose homeostasis following disruption of liver-projecting vagal sensory neurons, only male mice display increased insulin sensitivity. Furthermore, the loss of liver-projecting vagal sensory neurons limits the progression of hepatic steatosis in mice fed a steatogenic diet. Intriguingly, mice lacking liver-innervating vagal sensory neurons also exhibit less anxiety-like behavior compared to control mice. Therefore, modulation of the liver-brain axis may aid in designing effective treatments for both psychiatric and metabolic disorders associated with obesity and MAFLD.

BackgroundSleep plays a key role in glucose homeostasis and is an essential component of metabolic health. Sleep deprivation can induce hepatic steatosis and insulin resistance in mice, and these effects are thought to involve disruption of circadian metabolic regulation and neuroendocrine pathways. Sleep deprivation has also been associated with increased hepatic expression of elongation of very long chain fatty acids-like 3 (Elovl3). Because Elovl3 is involved in very-long-chain fatty acid synthesis and exhibits circadian regulation in the liver, we hypothesized that hepatic Elovl3 upregulation may contribute to sleep deprivation-induced lipid accumulation. This study aimed to investigate whether downregulation of hepatic Elovl3 expression influences hepatic lipid accumulation and glucose metabolism under sleep deprivation conditions.MethodsEleven-week-old male C57BL/6J mice were fed a high-fat diet and high-sucrose water for two weeks, followed by a single 6-hour period of sleep deprivation. To suppress hepatic Elovl3 expression, Elovl3-specific small interfering RNA (siRNA) was administered via tail vein injection (Elovl3 siRNA group), whereas control mice received non-coding siRNA (negative siRNA group). Hepatic triglyceride content, gene expression, gluconeogenesis (pyruvate challenge test), insulin sensitivity (insulin tolerance test), and glucose tolerance (intraperitoneal glucose tolerance test (ipGTT)) were evaluated. The primary outcome of this study was hepatic triglyceride accumulation after acute sleep deprivation. Secondary outcomes included glucose tolerance, gluconeogenesis, and insulin sensitivity.ResultsA single 6-hour sleep deprivation increased hepatic Elovl3 mRNA expression by 2.7-fold; this increase was completely suppressed 48 hours after administration of Elovl3 siRNA. Hepatic triglyceride content was significantly lower in the Elovl3 siRNA group than in the negative siRNA group after sleep deprivation (3.1 ± 1.5 vs 10.4 ± 4.2 mg/g tissue, respectively), corresponding to an approximate 70.4% reduction, under fasting and movement-restriction conditions following sleep deprivation. Hepatic gluconeogenesis did not differ between groups, whereas blood glucose levels at 30 minutes during ipGTT were significantly lower in the Elovl3 siRNA group.ConclusionsSuppression of hepatic Elovl3 expression attenuated sleep deprivation-induced hepatic steatosis in mice. However, although the blood glucose level at 30 minutes during ipGTT was significantly lower in the Elovl3 siRNA group, no significant differences were observed in glucose area under the curve during ipGTT, pyruvate challenge test, or insulin tolerance test, suggesting that additional interventions may be required to improve glucose intolerance associated with sleep deprivation. Hepatic Elovl3 may represent a potential therapeutic target for sleep deprivation-related metabolic dysfunction.

Nonalcoholic fatty liver disease is positively associated with obesity and cardiovascular disease risk. Apo-10'-lycopenoic acid (APO10LA), a potential oxidation product of apo-10'-lycopenal that is generated endogenously by β-carotene-9',10'-oxygenase (BCO2) cleavage of lycopene, inhibited hepatic steatosis in BCO2-expressing mice. The present study evaluated lycopene and APO10LA effects on hepatic steatosis in mice without BCO2 expression. Male and female BCO2-knockout (BCO2-KO) mice were fed a high saturated fat diet (HSFD) with or without APO10LA (10 mg/kg diet) or lycopene (100 mg/kg diet) for 12 wk. Lycopene or APO10LA supplementation reduced hepatic steatosis incidence (78% and 72%, respectively) and severity in BCO2-KO male mice. Female mice did not develop steatosis, had greater hepatic total cholesterol (3.06 vs. 2.31 mg/g tissue) and cholesteryl ester (1.58 vs. 0.86 mg/g tissue), but had lower plasma triglyceride (TG) (229 vs. 282 mg/dL) and cholesterol (97.1 vs. 119 mg/dL) than male mice. APO10LA-mitigated steatosis in males was associated with reduced hepatic total cholesterol (18%) and activated sirtuin 1 signaling, which resulted in reduced fatty acids (FAs) and TG synthesis markers [stearoyl-coenzyme A (CoA) desaturase protein, 71%; acetyl-CoA carboxylase phosphorylation, 79%; AMP-activated protein kinase phosphorylation, 67%], and elevated cholesterol efflux genes (cytochrome P450 family 7A1, 65%; ATP-binding cassette transporter G5/8, 11%). These APO10LA-mediated effects were not mimicked by lycopene supplementation. Intriguingly, steatosis inhibition by lycopene induced peroxisome proliferator-activated receptor (PPAR)α- and PPARγ-related genes in mesenteric adipose tissue (MAT) that increases mitochondrial uncoupling [cell death-inducing DNA fragmentation factor, α subunit-like effector a, 55%; PR domain-containing 16, 47%; uncoupling protein 3 (Ucp3), 55%], FA β-oxidation (PPARα, 53%; very long chain acyl-CoA dehydrogenase, 38%), and uptake (FA transport protein 4, 29%; lipoprotein lipase 43%). Expressions of 10 MAT PPAR-related genes were inversely correlated with steatosis score, suggesting that lycopene reduced steatosis by increasing MAT FA utilization. Our data suggest that lycopene and APO10LA inhibit HSFD-induced steatosis in BCO2-KO male mice through differential mechanisms. Sex disparity of BCO2-KO mice was observed in the outcomes of HSFD-induced liver steatosis and plasma lipids.

Hepatic SIRT1 Attenuates Hepatic Steatosis and Controls Energy Balance in Mice by Inducing Fibroblast Growth Factor 21

Liver sympathetic nerve activity and steatosis.

1903-P: Protective Effects of Linagliptin on Hepatic Steatosis in Mice Treated with Dual Inhibitor for Insulin Receptor and IGF-1 Receptor

Hepatic steatosis, a common liver disorder, can progress to severe conditions such as nonalcoholic steatohepatitis and cirrhosis. While olfactory receptors are primarily known for detecting odorants, emerging evidence suggests that they also influence liver lipid metabolism. This study generated a mouse model with a specific knockout of olfactory receptor 23 (MOR23) to investigate its role in hepatic steatosis. MOR23 knockout mice on a normal diet showed a slight increase in liver weight compared to wild‐type (WT) mice. When fed a high‐fat diet (HFD), these knockout mice exhibited accelerated hepatic steatosis, indicated by increased liver weight and hepatic triglyceride levels. Our findings suggest that the cyclic adenosine monophosphate/protein kinase A/AMP‐activated protein kinase pathway is involved in the role of MOR23, leading to the upregulation of peroxisome proliferator‐activated receptor α, peroxisome proliferator‐activated receptor‐γ coactivator 1‐α, and their target β‐oxidation genes in the liver. MOR23 also appeared to regulate lipogenesis and free fatty acid uptake in HFD‐fed mice, potentially by influencing sterol regulatory element‐binding protein 1 activity. Notably, administering a potential MOR23 ligand, cedrene, attenuated hepatic steatosis in WT mice, but these effects were largely nullified in MOR23 knockout mice. These findings provide valuable insights into the in vivo role of MOR23 in hepatic steatosis development.

A Novel Combination of Fruits and Vegetables Prevents Diet-Induced Hepatic Steatosis and Metabolic Dysfunction in Mice

In this study, we investigated the effect of sweroside (SOS)on hepatic steatosis in mice and elucidated its molecular mechanisms. We conducted in vivo experiments using a C57BL/6 mice model of nonalcohol fatty liver disease (NAFLD)to explore the effect of SOS on hepatic steatosis in NAFLD mice. In in vitro experiments, primary mouse hepatocyteswere treated with palmitic acidand SOS, and the protective effects of SOS on inflammation, lipogenesis, and fat deposition were analyzed. Autophagy-related protein levels and their related signaling pathways were evaluated in both in vivo and in vitro experiments. The results demonstrated that SOS decreased the high-fat-induced intrahepatic lipid content both in vivo and in vitro. The autophagy level in the liver was decreased in NAFLD mice but was reactivated following SOS intervention. SOS intervention was found to partially activate autophagy via the adenosine monophosphate-activated protein kinase (AMPK)/mammaliantarget of rapamycin (mTOR)signaling pathway. Consequently, when the AMPK/mTORpathway was suppressed or autophagy was inhibited, the beneficial effects of SOS intervention on hepatic steatosis were diminished. These results indicate that SOS intervention attenuates hepatic steatosis by promoting autophagy in the liver of NAFLD mice, in part by activating the AMPK/mTOR signaling pathway.

6-Gingerol regulates triglyceride and cholesterol biosynthesis to improve hepatic steatosis in MAFLD by activating the AMPK-SREBPs signaling pathway

1574-P: Catecholamine-Induced Adipose Lipolysis Drives Hepatic Steatosis in Pnpla3I148M Knockin Mice