原文支持、审慎不编造的高脂饮食肝脂肪变性纤维化骨质疏松与MAGL/CB1R引言讨论及PubMed英文标号引文

Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disease. Dietary supplementation has become a promising strategy for managing NAFLD. Hesperetin, a citrus flavonoid, is mainly found in citrus fruits (oranges, grapefruit, and lemons) and possesses multiple pharmacological properties, including anti-cancer, anti-Alzheimer and anti-diabetic effects. However, the anti-NAFLD effect and mechanisms of hesperetin remain unclear. In this study, we investigated the therapeutic effect of hesperetin against NAFLD and the underlying mechanism in vitro and in vivo. In oleic acid (OA)-induced HepG2 cells, hesperetin upregulated antioxidant levels (SOD/GPx/GR/GCLC/HO-1) by triggering the PI3 K/AKT-Nrf2 pathway, alleviating OA-induced reactive oxygen species (ROS) overproduction and hepatotoxicity. Furthermore, hesperetin suppressed NF-κB activation and reduced inflammatory cytokine secretion (TNF-α and IL-6). More importantly, we revealed that this anti-inflammatory effect is attributed to reduced ROS overproduction by the Nrf2 pathway, as pre-treatment with Nrf2 siRNA or an inhibitor of superoxide dismutase (SOD) or/and glutathione peroxidase (GPx) abolished hesperetin-induced NF-κB inactivation and reductions in inflammatory cytokine secretion. In a rat model of high-fat diet (HFD)-induced NAFLD, we confirmed that hesperetin relieved hepatic steatosis, oxidative stress, inflammatory cell infiltration and fibrosis. Moreover, hesperetin activated the PI3 K/AKT-Nrf2 pathway in the liver, increasing antioxidant expression and inhibiting NF-κB activation and inflammatory cytokine secretion. In summary, our results demonstrate that hesperetin ameliorates hepatic oxidative stress through the PI3 K/AKT-Nrf2 pathway and that this antioxidative effect further suppresses NF-κB-mediated inflammation during NAFLD progression. Thus, our study suggests that hesperetin may be an effective dietary supplement for improving NAFLD by suppressing hepatic oxidative stress and inflammation.

BACKGROUND AND AIMS Childhood obesity, with associated comorbidities such as non-alcoholic fatty liver disease (NAFLD), is a growing global health problem. Although lifestyle management is the mainstay of treatment, its efficacy on liver fibrosis has not yet been established. METHODS Children and adolescents admitted for severe obesity at a tertiary center (Zeepreventorium De Haan, Belgium) were enrolled in this prospective study. Intensive lifestyle therapy encompassed caloric restriction, physical activity, education on a healthy lifestyle and psychosocial support. At baseline, 6 and 12 months, liver ultrasound and transient elastography (TE) with controlled attenuation parameter (CAP) were performed to assess liver steatosis and fibrosis. RESULTS 204 patients (median age 14.0 years, BMI Z-score +2.8) were evaluated on admission. NAFLD on ultrasound was present in 71.1%, whereas 68.6% had CAP values ≥248 dB/m. 32.8% of patients had at least F2 fibrosis, including 10.3% with TE ≥9 kPa. After 6 months, median body weight loss was 16.0% in the 167 patients evaluated. Fibrosis improved in 75.0% (P<0.001). Baseline severity of liver fibrosis and steatosis were predictors of fibrosis resolution. 79 patients had reached the 1-year timepoint. The improvements were sustained, as fibrosis regressed at least one stage in all patients with baseline fibrosis. Fasting serum ALT and HOMA-IR decreased significantly over the 1-year period (P<0.001). CONCLUSION NAFLD and associated fibrosis are highly prevalent in children and adolescents with severe obesity. An intensive multidisciplinary lifestyle management program which causes significant weight loss not only improves liver steatosis, but also fibrosis.

Oxidized phosphatidylcholines (OxPCs) are implicated in chronic tissue damage. Hyperlipidemic LDL-R-–deficient mice transgenic for an OxPC-recognizing IgM fragment (scFv-E06) are protected against nonalcoholic fatty liver disease (NAFLD). To examine the effect of OxPC elimination at different stages of NAFLD progression, we used cre-dependent, adeno-associated virus serotype 8–mediated expression of the single-chain variable fragment of E06 (AAV8-scFv-E06) in hepatocytes of albumin-cre mice. AAV8-induced expression of scFv-E06 at the start of FPC diet protected mice from developing hepatic steatosis. Independently, expression of scFv-E06 in mice with established steatosis prevented the progression to hepatic fibrosis. Mass spectrometry–based oxophospho-lipidomics identified individual OxPC species that were reduced by scFv-E06 expression. In vitro, identified OxPC species dysregulated mitochondrial metabolism and gene expression in hepatocytes and hepatic stellate cells. We demonstrate that individual OxPC species independently affect disease initiation and progression from hepatic steatosis to steatohepatitis, and that AAV-mediated expression of scFv-E06 is an effective therapeutic intervention.

Our previous study showed that apple polyphenol extract (APE) ameliorated high-fat diet-induced hepatic steatosis in C57BL/6 mice by targeting the LKB1/AMPK pathway; to investigate whether other mechanisms are involved in APE induction of improved hepatic steatosis, especially the roles of bile acid (BA) metabolism and gut microbiota, we conducted this study. Thirty-three C57BL/6 male mice were fed with high-fat diet for 12 weeks and concomitantly treated with sterilized water (CON) or 125 or 500 mg/(kg·bw·day) APE (low-dose APE, LAP; high-dose APE, HAP) by intragastric administration. APE treatment decreased total fecal BA contents, especially fecal primary BA levels, mainly including cholic acid, chenodeoxycholic acid, and muricholic acid. An upregulated hepatic Farnesoid X receptor (FXR) protein level and downregulated protein levels of cholesterol 7α-hydroxylase (CYP7A1) and cholesterol 7α-hydroxylase (CYP27A1) were observed after APE treatment, which resulted in the suppressed BA synthesis. Meanwhile, APE had no significant effects on mucosal injury and FXR expression in the jejunum. APE regulated the diversity of gut microbiota and microbiota composition, characterized by significantly increased relative abundance of Akkermansia and decreased relative abundance of Lactobacillus. Furthermore, APE might affect the reverse cholesterol transport in the ileum, evidenced by the changed mRNA levels of NPC1-like intracellular cholesterol transporter 1 (Npc1l1), liver X receptor (Lxr), ATP binding cassette subfamily A member 1 (Abca1), and ATP binding cassette subfamily G member 1 (Abcg1). However, APE did not affect the dihydroxylation and taurine metabolism of BA. The correlation analysis deduced no obvious interactions between BA and gut microbiota. In summary, APE, especially a high dose of APE, could alleviate hepatic steatosis, and the mechanisms were associated with inhibiting BA synthesis and modulating gut microbiota.

The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has been increasing worldwide. Since gut-derived bacterial lipopolysaccharides (LPS) can travel via the portal vein to the liver and play an important role in producing hepatic pathology, it seemed possible that (1) LPS stimulates hepatic cells to accumulate lipid, and (2) inactivating LPS can be preventive. Acyloxyacyl hydrolase (AOAH), the eukaryotic lipase that inactivates LPS and oxidized phospholipids, is produced in the intestine, liver, and other organs. We fed mice either normal chow or a high-fat diet for 28 weeks and found that Aoah -/- mice accumulated more hepatic lipid than did Aoah +/+ mice. In young mice, before increased hepatic fat accumulation was observed, Aoah -/- mouse livers increased their abundance of sterol regulatory element-binding protein 1, and the expression of its target genes that promote fatty acid synthesis. Aoah -/- mice also increased hepatic expression of Cd36 and Fabp3 , which mediate fatty acid uptake, and decreased expression of fatty acid-oxidation-related genes Acot2 and Ppara . Our results provide evidence that increasing AOAH abundance in the gut, bloodstream, and/or liver may be an effective strategy for preventing or treating MASLD.

Monoacylglycerol (MAG) is an important bioactive lipid metabolite/intermediate, playing crucial roles in energy homeostasis and cellular signaling. This review explores MAG’s chemical structure, classification, and metabolic pathways. We also discuss the emerging evidence for MAG as a signaling molecule, with particular emphasis on their interactions with cannabinoid receptor 1 and cannabinoid receptor 2 and G-protein-coupled receptor 119. We focus on examining the diverse and tissue-specific functions of MAG in the context of metabolic diseases, including the roles of MAG in nutrient absorption, appetite regulation, obesity, glucose homeostasis, and lipid metabolism. Furthermore, we address therapeutic approaches in modulating MAG metabolism and challenges in development, considering the complexity of targeting peripheral tissues. This review provides insights into the multifaceted roles of MAG in metabolic health and disease, paving the way for novel therapeutic strategies in the management of metabolic disorders.

… 0.5 nM), which was highly selective against diacylglycerol lipase (DAGL), ABHD6, ABHD12, … Efficacy was demonstrated in models of acute liver injury, inflammation, and chemotherapy-…

Nonalcoholic fatty liver disease (NAFLD) represents one of the multifactorial complications of type 2 diabetes (T2D). The cannabinoid type 2 receptor (CB2R) plays a role in diabetes and diabetic complications; therefore, the aim of the present study was to investigate the role of β-caryophyllene (BCP), a CB2R agonist, in NAFLD associated with T2D and underlying CB2R-mediated pharmacological and molecular mechanisms. The murine model of T2D was developed by feeding male C57BL/6 J mice a high-fat diet along with streptozotocin (STZ) injections. After developing diabetes, the animals were orally administered BCP (50 mg/kg, p.o.) for 12 weeks. Treatment with BCP reduced the elevation of liver injury markers and inhibited the expression of NADPH oxidase 2 and NADPH oxidase 4, activating Nrf2 signaling and showing liver protective effects and mitigation of oxidative stress. BCP treatment also inhibited hepatic inflammation, as shown by inhibition of NOD-like receptor protein 3 inflammasome activation in T2D mice. Furthermore, treatment with BCP suppressed hepatic fibrosis and endothelial-to-mesenchymal transition by inhibiting transforming growth factor-β/suppressor of mothers against decapentaplegic (Smad) signaling. Taken together, BCP appears to efficiently improve liver function in diabetic mice by suppressing pathologic events of oxidative stress, inflammation, and fibrosis. To reveal the CB2R-dependent mechanism of BCP, the diabetic animals were pretreated with a CB2R antagonist, AM630, which is expected to abrogate the protective effects of BCP. Pretreatment with AM630 abolished the beneficial effects of BCP on hepatic oxidative stress, inflammation, and fibrosis, as well as liver function in T2D mice. These results demonstrate that BCP has the potential to be a novel agent of natural origin from cannabinoids, like compounds, for NAFLD associated with diabetes. The study is suggestive of therapeutic benefits of BCP and could be useful in nutraceutical and pharmaceutical development of BCP and a new in-class agent mediating CB2R activation for NAFLD with diabetes.

ABSTRACT Introduction Obesity is a chronic metabolic disease associated with insulin resistance, cardiometabolic complications, and increased mortality. Limitations of existing therapies have driven interests in alternative biological targets, including the endocannabinoid system and the cannabinoid-1 receptor (CB1R) signaling pathway. Areas covered This review examines the rationale for targeting peripheral CB1R signaling and summarizes preclinical and clinical evidence supporting peripherally restricted CB1R antagonists and inverse agonists for obesity and related metabolic disorders. The metabolic effects of CB1R blockade in peripheral tissues are discussed, as well as distinctions between central and peripheral CB1R inhibition. The article also reviews the current development landscape of CB1R-targeted compounds, including agents evaluated in early-phase clinical trials. Literature was identified through PubMed, Embase, and Scopus, supplemented by ClinicalTrials.gov. Expert opinion Peripherally restricted CB1R antagonists aim to deliver the metabolic benefits of CB1R blockade while avoiding the toxicity that ended development of centrally acting agents such as rimonabant. Recent phase 2 data with monlunabant demonstrated dose-dependent psychiatric adverse events and high discontinuation rates. Nimacimab, an antibody-based approach, has shown only marginal efficacy. The future of this drug class will therefore likely depend on rigorous long-term safety evaluation, biased CB1R pharmacology, and multitarget strategies including combinations with incretin-based therapies.

Iron overload-related liver injury is a major clinical problem in hereditary hemochromatosis, transfusional siderosis, and chronic liver diseases, yet current treatments such as iron chelation therapy and phlebotomy are limited by safety and efficacy issues. Cannabinoid receptor type 2 (CB2R) has been implicated in the regulation of iron metabolism, but its role and underlying mechanism in iron overload remain unclear. Here, we investigated whether CB2R can prevent liver damage caused by iron overload and explored its potential mechanism. Male C57BL/6J mice received 100 mg/kg iron-dextran intraperitoneally to establish an iron overload model. Liver damage and iron deposition were evaluated via histology, serum biochemistry, and molecular analyses. Further studies using primary hepatocytes and Kupffer cells exposed to ferric ammonium citrate (FAC) were performed to explore cell type-specific mechanisms in vitro. Pharmacological CB2R activation with the selective agonist JWH133 reduced liver iron deposition, oxidative stress, and inflammation, whereas CB2R-knockout (KO) exacerbated these phenotypes. Mechanistically, CB2R activation suppressed signal transducer and activator of transcription 3 (STAT3)-dependent hepcidin transcription in hepatocytes, thereby enhancing ferroportin 1 (FPN1)-mediated iron efflux. Concurrently, CB2R promoted nuclear factor erythroid 2-related factor 2 (Nrf2)/FPN1 signaling in Kupffer cells, decreasing the labile iron pool. These findings identify CB2R as a key regulator of hepatic iron homeostasis and suggest that targeting CB2R may offer a novel therapeutic strategy for iron overload-related diseases.

Human fibroblast growth factor 19 (FGF19) has become a potential therapeutic target for metabolic-related diseases. However, the effects of FGF19 on obesity-induced bone loss have not been completely elucidated. The aim of this study was to investigate the protective effects of FGF19 in high-fat diet (HFD)-fed obese mice and palmitic acid (PA)-treated osteoblasts and to further explore its underlying mechanisms. In vivo, we found that FGF19 alleviated the decreased bone mineral density (BMD) induced by HFD. Micro-CT analysis of femur samples and histological analysis indicated that FGF19 alleviated HFD-induced loss of bone trabeculae and damage to the bone trabecular structure. In vitro, the results suggested that FGF19 ameliorated the PA-induced decline in osteoblast proliferation, increased cell death and impaired cell morphology. Additionally, FGF19 protected against the decline in activation of alkaline phosphatase (ALP) and protein expression of Collagen-1, Runx-2, and osteopontin (OPN) induced by PA. Furthermore, FGF19 might enhance osteogenic differentiation via the Wnt/β-catenin pathway and inhibit osteoclastogenesis by regulating the osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL) axis, thus attenuating the negative effect of PA in osteoblasts. In conclusion, our results suggested that FGF19 might promote osteogenic differentiation partially through activation of the Wnt/β-catenin pathway and alleviate obesity-induced bone loss.

… The ratio of bone marrow fat might increase with menopause, aging, and chronic renal failure, resulting in decreased bone density and enhanced fracture risk [76]. A high-fat diet might …

Increased risks of skeletal fractures are common in patients with impaired glucose handling and type 2 diabetes mellitus (T2DM). The pathogenesis of skeletal fragility in these patients remains ill-defined as patients present with normal to high bone mineral density. With increasing cases of glucose intolerance and T2DM it is imperative that we develop an accurate rodent model for further investigation. We hypothesized that a high fat diet (60%) administered to developing male C57BL/6J mice that had not reached skeletal maturity would over represent bone microarchitectural implications, and that skeletally mature mice would better represent adult-onset glucose intolerance and the pre-diabetes phenotype. Two groups of developing (8 week) and mature (12 week) male C57BL/6J mice were placed onto either a normal chow (NC) or high fat diet (HFD) for 10 weeks. Oral glucose tolerance tests were performed throughout the study period. Long bones were excised and analysed for ex vivo biomechanical testing, micro-computed tomography, 2D histomorphometry and gene/protein expression analyses. The HFD increased fasting blood glucose and significantly reduced glucose tolerance in both age groups by week 7 of the diets. The HFD reduced biomechanical strength, both cortical and trabecular indices in the developing mice, but only affected cortical outcomes in the mature mice. Similar results were reflected in the 2D histomorphometry. Tibial gene expression revealed decreased bone formation in the HFD mice of both age groups, i.e., decreased osteocalcin expression and increased sclerostin RNA expression. In the mature mice only, while the HFD led to a non-significant reduction in runt-related transcription factor 2 (Runx2) RNA expression, this decrease became significant at the protein level in the femora. Our mature HFD mouse model more accurately represents late-onset impaired glucose tolerance/pre-T2DM cases in humans and can be used to uncover potential insights into reduced bone formation as a mechanism of skeletal fragility in these patients.

… TBS (< 1.350) despite normal bone mineral density. Regression analysis confirmed a strong … Hepatic steatosis was detected in all patients by liver US and confirmed by biopsy in 15 (…

… reductions in trabecular bone thickness (Tb.Th) (Fig. 3H) and trabecular bone mineral density (… In this study, we compared the impact of a diet (HFCF) that induced hepatic steatosis and …

… -related liver fibrosis, lower bone mineral density and degraded … common pathways underlying liver and bone involvement in … trabecular bone score (TBS) was used to assess the bone …

Objective Chronic liver diseases often involve metabolic damage to the skeletal system. The underlying mechanism of bone loss in chronic liver diseases remains unclear, and appropriate therapeutic options, except for orthotopic liver transplantation, have proved insufficient for these patients. This study aimed to investigate the efficacy and mechanism of transplantation of immature hepatocyte-like cells converted from stem cells from human exfoliated deciduous teeth (SHED-Heps) in bone loss of chronic liver fibrosis. Methods Mice that were chronically treated with CCl4 received SHED-Heps, and trabecular bone density, reactive oxygen species (ROS), and osteoclast activity were subsequently analyzed in vivo and in vitro. The effects of stanniocalcin 1 (STC1) knockdown in SHED-Heps were also evaluated in chronically CCl4 treated mice. Results SHED-Hep transplantation (SHED-HepTx) improved trabecular bone loss and liver fibrosis in chronic CCl4-treated mice. SHED-HepTx reduced hepatic ROS production and interleukin 17 (Il-17) expression under chronic CCl4 damage. SHED-HepTx reduced the expression of both Il-17 and tumor necrosis factor receptor superfamily 11A (Tnfrsf11a) and ameliorated the imbalance of osteoclast and osteoblast activities in the bone marrow of CCl4-treated mice. Functional knockdown of STC1 in SHED-Heps attenuated the benefit of SHED-HepTx including anti-bone loss effect by suppressing osteoclast differentiation through TNFSF11–TNFRSF11A signaling and enhancing osteoblast differentiation in the bone marrow, as well as anti-fibrotic and anti-ROS effects in the CCl4-injured livers. Conclusions These findings suggest that targeting hepatic ROS provides a novel approach to treat bone loss resulting from chronic liver diseases.

Objective: To evaluate the relationship between hepatic steatosis and bone mineral density (BMD) in children. Additionally, to assess 25-hydroxyvitamin D levels in the relationship between hepatic steatosis and BMD. Study design: A community-based sample of 235 children was assessed for hepatic steatosis, BMD, and serum 25-hydroxyvitamin D. Hepatic steatosis was measured by liver magnetic resonance imaging proton density fat fraction (MRI-PDFF). BMD was measured by whole-body dual-energy X-ray absorptiometry (DXA). Results: The mean age of the study population was 12.5 years (SD 2.5 years). Liver MRI-PDFF ranged from 1.1% to 40.1% with a mean of 9.3% (SD 8.5%). Across this broad spectrum of hepatic fat content, there was a significant negative relationship between liver MRI-PDFF and BMD Z-score (R=−0.421, p<0.001). Across the states of sufficiency, insufficiency and deficiency, there was a significant negative association between 25-hydroxyvitamin D and liver MRI-PDFF (p<0.05); however, there was no significant association between vitamin D status and BMD Z-score (p=0.94). Finally, children with clinically low BMD Z-scores were found to have higher ALT (p<0.05) and GGT (p<0.05) levels compared with children with normal BMD Z-scores. Conclusions: Across the full range of liver MRI-PDFF, there was a strong negative relationship between hepatic steatosis and BMD Z-score. Given the prevalence of NAFLD and the critical importance of childhood bone mineralization in protecting against osteoporosis, clinicians should prioritize supporting bone development in children with NAFLD.

Excessive toxic lipid accumulation in hepatocytes underlies the development of non-alcoholic fatty liver disease (NAFLD), phenotypically characterized by necrosis and steato-fibrosis, whose molecular mechanism is not yet fully understood. Patients with NAFLD display an imbalanced palmitic (PA) to oleic acid (OA) ratio. Moreover, increasing experimental evidence points out a relevant involvement of the exosomal content in disease progression. Aim of the study was to highlight the PA/OA imbalance within circulating exosomes, the subsequent intracellular alterations, and the impact on NALFD. Liver cells were challenged with exosomes isolated from both healthy subjects and NAFLD patients. The exosomal PA/OA ratio was artificially modified, and biological effects were evaluated. A NAFLD-derived exosomal PA/OA imbalance impacts liver cell cycle and cell viability. OA-modified NAFLD-derived exosomes restored cellular viability and proliferation, whereas the inclusion of PA into healthy subjects-derived exosomes negatively affected cell viability. Moreover, while OA reduced the phosphorylation and activation of the necroptosis marker, Receptor-interacting protein 1 (phospho-RIP-1), PA induced the opposite outcome, alongside increased levels of stress fibers, such as vimentin and fibronectin. Administration of NAFLD-derived exosomes led to increased expression of Elongase 6 (ELOVL6), Stearoyl-CoA desaturase 1 (SCD1), Tumor necrosis factor α (TNF-α), Mixed-lineage-kinase-domain-like-protein (MLKL) and RIP-1 in the hepatocytes, comparable to mRNA levels in the hepatocytes of NAFLD patients reported in the Gene Expression Omnibus (GEO) database. Genetic and pharmacological abrogation of ELOVL6 elicited a reduced expression of downstream molecules TNF-α, phospho-RIP-1, and phospho-MLKL upon administration of NAFLD-derived exosomes. Lastly, mice fed with high-fat diet exhibited higher phospho-RIP-1 than mice fed with control diet. Targeting the Elongase 6–RIP-1 signaling pathway offers a novel therapeutic approach for the treatment of the NALFD-induced exosomal PA/OA imbalance.

Monoacylglycerol lipase (MAGL), a member of the endocannabinoid system (ECS), plays a crucial role in physiological processes such as regulating the signal transduction of the ECS and the eicosanoid system. In recent years, MAGL has been validated as a potential therapeutic target for several human diseases. Small-molecule MAGL inhibitors have shown considerable promise for the treatment of neurodegenerative diseases, depression, and cancer, with several candidates having advanced to clinical trials. This review briefly outlines the structural features and physiological functions of MAGL, highlights the associations between MAGL and human diseases, and systematically discusses small-molecule MAGL inhibitors developed for different disorders, with the goal of providing a reference for the discovery of more potent MAGL inhibitors.

Monoacylglycerol lipase (MAGL) regulates endocannabinoid 2-arachidonoylglycerol (2-AG) and eicosanoid signalling. MAGL inhibition provides therapeutic opportunities but clinical potential is limited by central nervous system (CNS)-mediated side effects. Here, we report the discovery of LEI-515, a peripherally restricted, reversible MAGL inhibitor, using high throughput screening and a medicinal chemistry programme. LEI-515 increased 2-AG levels in peripheral organs, but not mouse brain. LEI-515 attenuated liver necrosis, oxidative stress and inflammation in a CCl4-induced acute liver injury model. LEI-515 suppressed chemotherapy-induced neuropathic nociception in mice without inducing cardinal signs of CB1 activation. Antinociceptive efficacy of LEI-515 was blocked by CB2, but not CB1, antagonists. The CB1 antagonist rimonabant precipitated signs of physical dependence in mice treated chronically with a global MAGL inhibitor (JZL184), and an orthosteric cannabinoid agonist (WIN55,212-2), but not with LEI-515. Our data support targeting peripheral MAGL as a promising therapeutic strategy for developing safe and effective anti-inflammatory and analgesic agents.

The aim of this study was to investigate the relationship between prevalence and risks of osteoporosis or osteoporotic fracture and NAFLD. Patients with NAFLD should be monitored regularly for bone mineral density and bone metabolism indicators to prevent osteoporosis or osteoporotic fractures. The aim of this meta-analysis was to investigate the relationship between prevalence and risks of osteoporosis or osteoporotic fracture and non-alcoholic fatty liver disease (NAFLD). Five databases, including PubMed, Web of Science, Embase, Scopus and Cochrane Library, were searched since the conception of these databases until December 2021. The cohort studies, cross-sectional analyses or case–control studies evaluating the relationship between osteoporosis or osteoporotic fracture and NAFLD were retrieved from these databases. Relevant data were extracted from the included studies, and a meta-analysis was performed. A total of seven studies were included. The prevalence of osteoporosis or osteoporotic fractures was higher in the NAFLD group than in the non-NAFLD group [OR = 1.17, 95%CI(1.04,1.31)], while the prevalence of osteoporosis was higher in the NAFLD group than in the non-NAFLD group [OR = 1.46, 95%CI (1.21,1.77) and OR = 1.48, 95%CI (1.31,1.68), respectively] in men and women. The risk of osteoporosis or osteoporotic fractures was higher in the NAFLD group than in the non-NAFLD group [OR = 1.33,95%CI (1.24,1.44) and OR = 1.57,95%CI (1.08,2.29), respectively]. The risk of osteoporosis or osteoporotic fractures was higher in male and female NAFLD groups than that in the non-NAFLD group [OR = 1.29, 95%CI(1.14,1.47) and OR = 1.36, 95%CI (1.25,1.48), respectively]. After parameter adjustment, the risk of osteoporosis or osteoporotic fracture was higher in the male NAFLD group than in the non-NAFLD group [OR = 2.10, 95%CI(1.36,3.25)], while no significant difference was found among women [OR = 1.13, 95%CI (0.86,1.48)]. The prevalence and risk of osteoporosis or osteoporotic fractures were significantly associated with NAFLD in men and women. Trial registration: PROSPERO 2022 CRD42022304708

… increase the risk of osteoporosis, it was not necessarily beneficial for bone metabolism. In this study, we only investigated the relationship between MAFLD and bone mass but not the …