Immune modulating effects of additional supplementation of estradiol combined with testosterone in murine testosterone-deficient NAFLD model.

Nonalcoholic fatty liver disease (NAFLD) is associated with testosterone deficiency. However, NAFLD patients generally do not respond to treatment with testosterone alone. We investigated the innate immune mechanisms underlying the effects of treatment with testosterone alone, estrogen alone, or combined testosterone and estrogen on high-fat diet (HFD)-induced NAFLD due to testosterone deficiency. Orchiectomized (OCX) male Rag2-/- mice were used as a model of testosterone deficiency. To assess NAFLD severity, NAFLD activity score (NAS) is adopted. Moreover, immunological change was analyzed by multicolor flow cytometry. Treatment with both testosterone and estrogen significantly decreased body weight to that of the sham mice/normal diet (ND). NAS and liver fibrosis in OCX-HFD mice were significantly deteriorated, and treatment with testosterone and estrogen improved same as sham-ND mice. HFD increased the ratio of both type 2 and 3 innate lymphoid cells (ILC2s and ILC3s) to CD45-positive cells in the liver. Treatment with testosterone alone decreased the ratio of ILC2 to CD45 but not the ILC3-to-CD45 ratio. Addition of estrogen to the treatment reduced the ratios of ILC2-to-CD45 and ILC3-to-CD45 to the same level observed in sham-HFD mice. Moreover, OCX-HFD mice had a decreased proportion of M2 macrophages compared with sham-ND mice. Treatment with testosterone alone did not restore the proportion of M2 macrophages; however, combination treatment with both estrogen and testosterone increased that to the same level as that in sham-HFD mice. Treatment with both testosterone and estrogen improves liver fibrosis and decreases ILC3 and increases M2 macrophage abundance in the liver.NEW & NOTEWORTHY The progression of nonalcoholic fatty liver disease (NAFLD) is associated with testosterone deficiency. NAFLD patients generally do not respond to treatment with testosterone alone. In animal studies, treatment with testosterone and estrogen reduced the ratios of ILC2:CD45 and ILC3:CD45 and increased M2 macrophages in liver. Our study suggests, based on our immunological data, that a combination of estrogen and testosterone may be clinically relevant for the treatment of NAFLD in patients with male menopause.

A Pilot Study on the Effect of Anti-Thrombopoietin Antibody on Platelet Count in Patients with Type 2 Diabetes.

Thrombopoietin (THPO) is a circulatory cytokine that plays an important role in platelet production. The presence of anti-THPO antibody relates to thrombocytopenia and is rarely seen in hematopoietic and autoimmune diseases. To date, there had been no reports that focused on the anti-THPO antibody in patients with type 2 diabetes mellitus (T2DM). To evaluate prevalence of the anti-THPO antibody in patients with T2DM and the relationship between anti-THPO antibody and platelet count, a cross-sectional study was performed on 82 patients with T2DM. The anti-THPO antibody was measured by ELISA using preserved sera and detected in 13 patients. The average platelet count was significantly lower in patients with the anti-THPO antibody than in those without the anti-THPO antibody. Multivariate linear regression analyses showed a significant relationship between the anti-THPO antibody and platelet count, after adjusting for other variables. To our best knowledge, this was the first report on the effect of the anti-THPO antibody on platelet count in patients with T2DM. Further investigation is needed to validate the prevalence and pathological significance of the anti-THPO antibody in patients with T2DM.

The sodium-glucose cotransporter 2 inhibitor luseogliflozin can suppress muscle atrophy in Db/Db mice by suppressing the expression of foxo1.

We investigated the effect of the sodium glucose cotransporter-2 inhibitor (SGLT-2i) luseogliflozin on skeletal muscle. Eight-week-old mice were fed a standard diet or the standard diet with added luseogliflozin for 8 weeks. The mice were divided into the following four genotype/dietary groups: Db/m mice without SGLT-2i, Db/m mice with SGLT-2i inhibitor, Db/Db without SGLT-2i, and Db/Db with SGLT-2i. Among the mice with and without SGLT-2i, the ratio of soleus and plantaris muscle to body weight in the Db/Db mice was significantly lower than that in the Db/m mice. The cross-sectional area of soleus muscle in the Db/Db mice without SGLT-2i was significantly higher than that in the Db/Db mice with SGLT-2i. The expression of foxo1 in soleus muscle of the Db/Db mice was significantly higher than that of the Db/m mice, and the foxo1 expression of the Db/Db mice with SGLT-2i was significantly lower than that of the mice without SGLT-2i. The fluorescence intensity of foxo1 in the Db/Db mice fed SGLT-2i was significantly lower than that in the Db/Db mice without SGLT-2i. The administration of luseogliflozin resulted in the suppression of both the increased foxo1 expression and the reduced muscle cross-sectional area in the soleus muscle of Db/Db mice.

Late-night-dinner is associated with poor glycemic control in people with type 2 diabetes: The KAMOGAWA-DM cohort study.

Skipping breakfast or irregular breakfast is associated with poor glycemic control. However, a relationship between the timing of dinner and glycemic control in people with type 2 diabetes remains indefinite. Therefore, we investigated the relationship between late-night-dinner and glycemic control in people with type 2 diabetes. We performed questionnaire survey for lifestyle factors in this cross-sectional study. We defined having dinner later than eight pm as late-night-dinner. We examined the differences in clinical and metabolic parameters between those who have late-night-dinner and those who do not have. We also examined the relationship between late-night-dinner and HbA1c, using multiple regression analysis. Ninety-five people (23.2%) had a late-night-dinner, among 409 people with type 2 diabetes. Metabolic parameters (mean (SD) or median (interquartile range)) of people with late-night-dinner were worse than those of without, including body mass index (BMI) (24.4 (4.0) vs. 23.2 (3.4) kg/m2, p = 0.006), triglycerides (1.5 (1.1-2.1) vs. 1.2 (0.8-1.7) mmol/L, p < 0.001), HDL-cholesterol (1.4 (0.4) vs. 1.6 (0.4) mmol/L, p = 0.004) and hemoglobin A1c (58.1 (13.3) vs. 55.2 (10.2) mmol/mol, (7.5 (1.2) vs. 7.2 (0.9) %), p = 0.023)). Late-night-dinner (standardized regression coefficient = 0.13, p = 0.028) was associated with hemoglobin A1c after adjusting for age, BMI, sex, duration of diabetes, smoking, exercise, alcohol, snacking after dinner, nighttime sleep duration, time from dinner to bedtime, skipping breakfast, and medication for diabetes. Late-night-dinner is independently associated with poor glycemic control in people with type 2 diabetes.

Dipeptidyl peptidase-4 inhibitors have adverse effects for the proliferation of human T cells.

Dipeptidyl peptidase-4 (DPP-4) is a critical molecule for the metabolism of incretins. In addition, DPP-4 is known as CD26, the receptor of T cells, and plays important role in activation of T cells. Recently, DPP-4 inhibitors (DPP4i) are reported to have several immunologic effects beyond glycemic control. DPP4i seem to have anti-inflammatory effects in patients with type 2 diabetes. This might be direct effects on T cells. However, the close mechanism is not clear. To evaluate the possibility, we performed ex vivo assays by using primarily human CD4+ T cells (CD4) and CD8+ T cells (CD8). We purified primary naïve CD4 and CD8 from human peripheral blood. Then, we evaluated the effect of DPP4i on the proliferation of naïve T cells and the cytokine production in ex vivo experiments. The proliferation of CD4 and CD8 were suppressed by adding DPP4i in a dose dependent manner. However, DPP4i did not inhibit cytokine production from CD4. It was revealed by phospho-flow that the T cell receptor (TCR) signaling was attenuated in the presence of DPP4i. Taken together, DPP4i modulated TCR signaling, which contributed to attenuate the proliferation of CD4 and CD8. DPP4i have adverse effects for the proliferation of human T cells.

Impact of fatty liver disease and metabolic syndrome on incident type 2 diabetes; a population based cohort study.

Fatty liver disease and metabolic syndrome (MetS) are both shown to increase the risk of type 2 diabetes. The aim of this study was to investigate the combined effect of fatty liver and MetS on incident diabetes. In this cohort study of 17,810 participants, fatty liver was diagnosed by abdominal ultrasonography and MetS was defined by a joint interim statement. We divided the participants into four groups according to the presence of fatty liver and/or MetS. Type 2 diabetes was defined as HbA1c ≥6.5%, fasting plasma glucose ≥7.0 mmol/L or treatment for diabetes. During the follow up examination (median 5.1 years), 804 participants developed diabetes. Compared with non-MetS without fatty liver, hazard ratios (HR) for incident diabetes after adjusting for age, body mass index, smoking status, exercise habit, alcohol consumption, family history of diabetes logarithm of alanine aminotransferase and fasting plasma glucose, were as follow: 2.35 (95 % CI 1.91-2.89, p<0.001) in non-MetS with fatty liver, 1.70 (95% CI 1.30-2.20, p<0.001) in MetS without fatty liver, and 2.33 (95% CI 1.85-2.94, p<0.001) in MetS with fatty liver. In addition, adjusted HRs for incident diabetes compared with MetS without fatty liver were 1.39 (95% CI 1.07-1.80, p=0.012) in non-MetS with fatty liver and 1.38 (95% CI 1.07-1.79, p=0.013) in MetS with fatty liver. Fatty liver affects more on the risk of incident diabetes than MetS. To prevent the further risk of diabetes, we should pay more attention to fatty liver.

The role of root size versus root efficiency in phosphorus acquisition in rice.

In rice, genotypic differences in phosphorus (P) uptake from P-deficient soils are generally proportional to differences in root biomass or surface area (RSA). It is not known to what extent genotypic variation for root efficiency (RE) exists or contributes to P uptake. We evaluated 196 rice accessions under P deficiency and detected wide variation for root biomass which was significantly associated with plant performance. However, at a given root size, up to 3-fold variation in total biomass existed, indicating that genotypes differed in how efficiently their root system acquired P to support overall plant growth. This was subsequently confirmed, identifying a traditional genotype, DJ123, with 2.5-fold higher RE (32.5 µg P cm(-2) RSA) compared with the popular modern cultivar IR64. A P depletion experiment indicated that RE could not be explained by P uptake kinetics since even IR64 depleted P to <20nM. A genome-wide association study identified loci associated with RE, and in most cases the more common marker type improved RE. This may indicate that modern rice cultivars lost the ability for efficient P uptake, possibly because they were selected under highly fertile conditions. One association detected on chromosome 11 that was present in a small group of seven accessions (including DJ123) improved RE above the level already present in many traditional rice accessions. This subspecies is known to harbor genes enhancing stress tolerance, and DJ123 may thus serve as a donor of RE traits and genes that modern cultivars seem to have lost.

Triglycerides to high-density lipoprotein cholesterol ratio is an independent predictor of incident fatty liver; a population-based cohort study.

BACKGROUND: Triglycerides (TG) to high-density lipoprotein cholesterol (HDL-C) ratio (TG/HDL-C) has been recommended for surrogates of insulin resistance. However, it remains to be elucidated the association between TG/HDL-C and incident fatty liver. AIMS: To investigate the association between TG/HDL-C and incident fatty liver. METHODS: We performed population-based historical cohort study consisted with 4518 healthy Japanese who received yearly health-checkup programmes over decade. Fatty liver was diagnosed using ultrasonography. RESULTS: During the observation periods, 38.8% (case/N = 1023/2637) of men and 17.2% (case/N = 324/1881) of women developed fatty liver. Adjusting odds ratio of TG/HDL-C for incident fatty liver were 1.59 (95% confidence interval (CI) 1.42-1.79, P < 0.0001) in men and 2.50 (95% CI 1.80-3.51, P < 0.0001) in women. In addition, adjusting odds ratio of TG/HDL-C for incident non-alcoholic fatty liver disease were 1.55 (95% CI 1.35-1.77, P < 0.0001) in men and 2.72 (95% CI 1.88-3.95, P < 0.0001) in women. According to the receiver operator characteristic (ROC) analysis, the optimal cut-off point of TG/HDL-C for incident fatty liver was 0.88 (area under the ROC curve (AUC) 0.67 [95% CI 0.65-0.69], sensitivity = 0.64, specificity = 0.60, P < 0.0001) in men and 0.64 (AUC 0.69 [95% CI 0.66-0.72], sensitivity = 0.50, specificity = 0.78, P < 0.0001) in women. CONCLUSIONS: The TG/HDL-C could predict the incident fatty liver. Thus, it is important to check TG/HDL-C and lifestyles modification is needed for preventing future fatty liver disease in patients with high TG/HDL-C.

The impact of non-alcoholic fatty liver disease on incident type 2 diabetes mellitus in non-overweight individuals.

BACKGROUND & AIMS: The aim of this study was to evaluate the impact of non-alcoholic fatty liver disease (NAFLD) on incident type 2 diabetes mellitus (T2DM) in non-overweight individuals with NAFLD. METHODS: A population-based retrospective cohort study of 4629 participants who were enrolled in a health check-up programme for more than 10 years. A standardized questionnaire and abdominal ultrasonography were used to diagnose NAFLD. A cut-off point of BMI 23 kg/m(2) was used to define overweight (≥23.0 kg/m(2)) or non-overweight (<23.0 kg/m(2)). The primary outcome was incident T2DM. RESULTS: Over a mean follow-up of 12.8 years, 351 participants (7.6%) developed T2DM. The incidence rate of T2DM was 3.2% in the non-overweight without NAFLD group, 14.4% in the non-overweight with NAFLD group, 8.0% in the overweight without NAFLD group and 26.4% in the overweight with NAFLD group. The adjusted hazard ratios for incident T2DM compared with the non-overweight without NAFLD group were as follows: 3.59 (95% CI: 2.14-5.76) in the non-overweight with NAFLD group, 1.99 (95% CI: 1.47-2.69) in the overweight without NAFLD group and 6.77 (95% CI: 5.17-8.91) in the overweight with NAFLD group. The adjusted hazard ratio in the non-overweight with NAFLD group was significantly higher than that in the overweight without NAFLD group or that in the non-overweight without NAFLD group. CONCLUSIONS: Non-overweight individuals with NAFLD had a high risk of incident T2DM. Diagnosis of NAFLD is important in non-overweight individuals, and therefore it might be necessary to follow their health conditions on a long-term basis after detection of NAFLD.

Impact of low-carbohydrate diet on renal function: a meta-analysis of over 1000 individuals from nine randomised controlled trials.

We aimed to clarify the effect of low-carbohydrate diet (LCD) on renal function in overweight and obese individuals without chronic kidney disease (CKD). Literature searches were performed using EMBASE, MEDLINE and Cochrane Library until December 2015. We selected articles that reported human studies from their inception until December 2015 in English using the following searching terms: 'Low carbohydrate diet' AND ('Clinical trial' OR 'Clinical study' OR 'Clinical investigation' OR 'Observational study' OR 'Cohort study'). We compared the effects of LCD on renal function, defined as change in estimated glomerular filtration rate (eGFR), assessed in randomised-controlled trials. We calculated the mean change in eGFR and the mean change in standard deviations by eGFR or creatinine clearance, and compared the mean change in eGFR and standard deviations in LCD with those in the control diet using fixed-effects models. We selected nine randomised controlled trials including 1687 participants (861 were fed LCD and 826 were fed the control diet). The mean change in eGFR in the LCD group was -4·7 to 24·0 ml/min per 1·73 m2 and that in the control diet group was -4·1 to 10·8 ml/min per 1·73 m2. The mean change in eGFR in the LCD group was greater than that in the control diet (0·13 ml/min per 1·73 m2; 95 % CI 0·00, 0·26). In the present meta-analysis, we identified that the increase in eGFR was greater in LCD compared with the control diet in overweight and obese individuals without CKD.

The relationship between hepatic steatosis and skeletal muscle mass index in men with type 2 diabetes.

Recent cross-sectional studies revealed that sarcopenia is associated with non-alcoholic fatty liver disease (NAFLD) in general population. However, it remains to be elucidated that the association between skeletal muscle mass index (SMI) and hepatic steatosis in patients with type 2 diabetes. In this cross-sectional study of 145 Japanese patients (79 men and 66 women) with type 2 diabetes, we examined the correlation of SMI with hepatic steatosis. Skeletal muscle mass was estimated from bioimpedance analysis measurements and SMI (%) was defined as skeletal muscle mass (kg)/total body weight (kg) × 100. Controlled attenuation parameter (CAP) evaluated with transient elastography, was used for assessment of hepatic steatosis. In addition, we also investigated the association between SMI and prevalence of NAFLD, which was defined as CAP over 237.8 dm-1, using logistic regression analysis. Fifty-eight (74%) men and thirty-nine (60%) women had NAFLD. Multiple regression analysis demonstrated that SMI was independently correlated with CAP (ß = -0.35, P = 0.007) in men after adjusting for age, body mass index, hemoglobin A1c, triglycerides/ HDL-C ratio, C-reactive protein and gamma-glutamyl transferase. On the other hand, SMI was not associated with CAP in women. Odds ratio per incremental 1% of SMI for prevalence of NAFLD was 0.80 (95% CI 0.64-0.97, P = 0.021) after adjusting for age, BMI, smoking statues, triglycerides/ HDL-C ratio, HbA1c, and gamma-glutamyl transferase in men. In conclusion, SMI was negatively associated with hepatic steatosis in men with type 2 diabetes.

Anti-barnacle Activity of Isocyanides Derived from Amino Acids.

Creation of new potent antifouling active compounds is important for the development of environmentally friendly antifouling agents. Fifteen isocyanide congeners derived from proteinogenic amino acids were synthesized, and the antifouling activity and toxicity of these compounds against cypris larvae of the barnacle Balanus amphitrite were investigated. All synthesized amino acid-isocyanides exhibited potent anti-barnacle activity with EC50 values of 0.07 - 10.34 µg/ml after 120 h exposure without significant toxicity. In addition, seven compounds showed more than 95% settlement inhibition of the cypris larvae at 10 µg/ml after 120 h exposure without any mortality observed. Considering their structure, these amino acid-isocyanides would eventually be biodegraded to their original nontoxic amino acids. These should be useful for further research focused on the development of environmentally friendly antifoulants.

Range of protein induced by vitamin K absence or antagonist-II levels in neonates at birth.

Protein induced by vitamin K absence or antagonist-II (PIVKA-II) is avitamin K (VK) deficiency indicator in neonates. However, PIVKA-II detection frequency in neonatal blood at birth and the correlation between PIVKA-II and gestational age are unclear. We retrospectively analyzed infants admitted to our institution between June 1, 2018, and March 31, 2022, whose clinical and PIVKA-II data were available, and classified them into preterm and term infant groups. Overall incidence of PIVKA-II-positive cases (≥ 50 mAU/mL) was 42.8%, including 0.6% apparent VK deficiency (≥ 5000 mAU/mL), 3.1% experimental VK deficiency (1000-4999 mAU/mL), and 10.7% latent VK deficiency (200-999 mAU/mL) cases. Incidence of PIVKA-II-positive cases was significantly higher in the term group than in the preterm group (49.4% vs. 29.7%, p < 0.001). Gestational age correlated with PIVKA-II levels (r2 = 0.117, p < 0.0001). Median serum PIVKA-II levels and incidence of PIVKA-II-positive cases (≥ 50 mAU/mL, 16.4%) were lower at 5 days after birth than at birth, possibly reflecting the postnatal VK prophylaxis impact. Only one infant was diagnosed with VK deficiency bleeding (PIVKA-II levels, at birth: 10,567 mAU/mL; at day 5: 2418 mAU/mL). Thus, serum PIVKA-II levels after birth weakly correlated with gestational age. VK deficiency was more common in term infants than in preterm infants.

Clinical Practice Guidelines for the Management of Congenital Cytomegalovirus Infection in Japan 2023: Executive Summary.

Congenital cytomegalovirus (cCMV) infection is the most common congenital infection in developed countries. Although a standard therapy has not yet been established, evidence for the management of cCMV infection has been accumulating. The first edition of the "Clinical Practice Guidelines for the Management of Congenital Cytomegalovirus Infection" was published in Japan in 2023. This summary outlines the clinical questions (CQs) in the guidelines, with reference to the Japanese Medical Information Distribution Service Manual. Overall, 20 CQs with statements regarding prenatal risk assessment, prevention and management at diagnosis (CQs 1-1-1-3), diagnosis (CQs 2-1-2-6), treatment (CQs 3-1-3-7) and follow-up requirements (CQs 4-1-4-4) have been discussed. For each statement, the levels of recommendation, evidence and consensus rates were determined. These guidelines will assist in the management of patients with cCMV infection.

Improvement of insulin resistance, blood pressure and interstitial pH in early developmental stage of insulin resistance in OLETF rats by intake of propolis extracts.

Propolis, a resinous mixture collected from plants by the Apis mellifera bee, contains high level nutrient factors including vitamins, polyphenols, and amino acids that would be expected to improve insulin sensitivity. Insulin resistance would secondarily cause elevation of blood pressure and increase the risk of cardiovascular diseases. The purpose of this study is to investigate the effect of propolis extracts on blood glucose levels and blood pressures in an early developmental stage of insulin resistance in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. OLETF rats (10 weeks old) were divided into three different groups: normal diet, 0.1% propolis diet, and 0.5% propolis diet. After 8 weeks, blood glucose levels, blood pressures, plasma metabolic factors and hormones, and interstitial fluid pH were measured. Casual blood glucose levels were decreased associated with a reduction of plasma insulin levels in both propolis diet groups compared with normal diet group. Propolis decreased systolic blood pressure with no significant changes in plasma aldosterone levels. We also found that interstitial fluid pH in ascites, liver, and skeletal muscle was higher in rats fed propolis diet than rats fed normal diet. These data suggests that dietary propolis improves insulin sensitivity and blood pressures in the early stage of the process in development of insulin resistance, which may be mediated by suppression of metabolic acidosis.

Phosphoenolpyruvate carboxylase intrinsically located in the chloroplast of rice plays a crucial role in ammonium assimilation.

Phosphoenolpyruvate carboxylase (PEPC) is a key enzyme of primary metabolism in bacteria, algae, and vascular plants, and is believed to be cytosolic. Here we show that rice (Oryza sativa L.) has a plant-type PEPC, Osppc4, that is targeted to the chloroplast. Osppc4 was expressed in all organs tested and showed high expression in the leaves. Its expression in the leaves was confined to mesophyll cells, and Osppc4 accounted for approximately one-third of total PEPC protein in the leaf blade. Recombinant Osppc4 was active in the PEPC reaction, showing V(max) comparable to cytosolic isozymes. Knockdown of Osppc4 expression by the RNAi technique resulted in stunting at the vegetative stage, which was much more marked when rice plants were grown with ammonium than with nitrate as the nitrogen source. Comparison of leaf metabolomes of ammonium-grown plants suggested that the knockdown suppressed ammonium assimilation and subsequent amino acid synthesis by reducing levels of organic acids, which are carbon skeleton donors for these processes. We also identified the chloroplastic PEPC gene in other Oryza species, all of which are adapted to waterlogged soil where the major nitrogen source is ammonium. This suggests that, in addition to glycolysis, the genus Oryza has a unique route to provide organic acids for ammonium assimilation that involves a chloroplastic PEPC, and that this route is crucial for growth with ammonium. This work provides evidence for diversity of primary ammonium assimilation in the leaves of vascular plants.

Acid-mediated intermolecular C-F/C-H cross-coupling of 2-fluorobenzofurans with arenes: synthesis of 2-arylbenzofurans.

Transition-metal-free acid-promoted biaryl construction was achieved via intermolecular C-F/C-H cross-coupling. By treating 2-fluorobenzofurans with arenes in the presence of AlCl3, 2-arylbenzofurans were obtained. This protocol was successfully applied to the short-step orthogonal synthesis of a bioactive 2-arylbenzofuran natural product, which allows independent transformations of C-F and C-Br bonds. Mechanistic studies indicated that α-fluorine-stabilized carbocations, generated via the protonation of 2-fluorobenzofurans, served as key intermediates. The Friedel-Crafts-type C-C bond formation between the α-fluorocarbocations and arenes, followed by hydrogen fluoride elimination, afforded 2-arylbenzofurans.

Group 3 Innate Lymphoid Cells Protect Steatohepatitis From High-Fat Diet Induced Toxicity.

Background and Aims: Emerging evidence has revealed that innate lymphoid cells (ILCs) play a key role in regulating metabolic disorders. Here, we investigated the role of group 3 ILCs (ILC3s) in the modulation of Non-alcoholic fatty liver disease (NAFLD). Methods: RORγ gfp/gfp (RORgt KI/KI) and Rag2-/- mice with the administration of A213, RORgt antagonist, fed with a high-fat-diet (HFD) for 12 weeks, were used. We performed flow cytometry, real time PCR, and lipidomics analysis of serum and liver, and used RAW264.7 cells and murine primary hepatocytes in vitro. Results: HFD increased ILC3s and M1 macrophages in the liver, and RORgt KI/KI mice deficient in ILC3 showed significant fatty liver, liver fibrosis and significantly increased palmitic acid levels in serum and liver. In addition, administration of A213 to Rag2-/- mice caused significant fatty liver, liver fibrosis, and a significant increase in serum and liver palmitate concentrations, as in RORgt KI/KI mice. Addition of palmitc acid stimulated IL-23 production in cell experiments using RAW264.7. IL-22 produced by ILC3s inhibited the palmitate-induced apoptosis of primary hepatocytes. Conclusions: HFD stimulates IL-23 production by M1 macrophages, thus promoting ILC3 proliferation, whereas IL-22 secreted by ILC3s contributes to the upregulation of hepatic lipid metabolism and has anti-apoptosis activity.