Loss of immunity-related GTPase GM4951 leads to nonalcoholic fatty liver disease without obesity

Zhang, Zhao; Rong, Shunxing; Yan, Lijuan; SoRelle, Jeffrey A.; Li, Xiaohong; Tang, Miao; Keller, Katie; Ludwig, Sara; Moresco, Eva Marie Y.; Beutler, Bruce

doi:10.1038/s41467-022-31812-4

Cited by 10 publications

(6 citation statements)

References 46 publications

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“…Mouse primary hepatocytes were isolated following a 2-step collagenase digestion protocol (20). Briefly, mice were anesthetized and the liver was perfused in situ with 50 ml Hank's Balanced Salt Solution (HBSS) through the portal vein, followed by 8 mL of liver digestion media containing 2M HEPES, 1% Penicillin-Streptomycin (P/S) Solution, and 0.08% type 4 collagenase.…”

Section: Primary Hepatocyte Isolationmentioning

confidence: 99%

Metabolic effects of CCL5 deficiency in lean and obese mice

et al. 2023

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Accumulation and activation of immunocytes in adipose tissues are essential to obesity-induced inflammation and insulin resistance. Chemokines are pivotal for the recruitment of immunocytes in adipose tissue during obesity. Chemokine (C-C motif) ligand 5 (CCL5) plays a vital role in the recruitment of immunocytes to sites of inflammation. CCL5 expression level is increased in obese adipose tissue from humans and mice. However, the role of CCL5 in obesity-induced adipose inflammation remains unclear. Our study found that the CCL5 expression level was increased in the epididymal white adipose tissue (eWAT) of obese mice, particularly in CD8+ T cells. CCL5 knockout (KO) mice exhibited better glucose tolerance than wild-type (WT) mice under lean conditions. In contrast, CCL5 KO mice were more insulin resistant and had severe hepatic steatosis than WT mice under obese conditions. Increased T cells in adipose tissue heaven adipose inflammation in obese CCL5 KO mice. The compensatory increased T cell-associated chemokines may account for increased T cell content in the eWAT of obese CCL5 KO mice. These findings imply that CCL5 deficiency exacerbates adipose inflammation and impairs insulin sensitivity in the metabolic tissues of obese mice.

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Section: Primary Hepatocyte Isolationmentioning

confidence: 99%

Metabolic effects of CCL5 deficiency in lean and obese mice

et al. 2023

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“…In terms of genetic factors, GM4951, an immunity-related GTPase, can regulate liver lipid metabolism. Experiments show that a deficiency in GM4951 can lead to “lean” NAFLD [ 37 ]. Our results showed that TG only mediated about 2.98% of the positive correlation between BMI and non-obese NAFLD, indicating the involvement of other mechanisms mediating BMI and non-obese NAFLD.…”

Section: Discussionmentioning

confidence: 99%

Triglycerides Mediate the Influence of Body Mass Index on Non-Alcoholic Fatty Liver Disease in a Non-Obese Chinese Population with Normal Low-Density Lipoprotein Cholesterol Levels

Han,

Kong,

Zhang

et al. 2024

Obes Facts

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Introduction: Over 25% of the world's population has non-obese or lean non-alcoholic fatty liver disease (NAFLD) and the prevalence is higher than average in Asia. The present study focused on the relationship between body mass index(BMI) and non-obese NAFLD in non-overweight people in China, particularly the influence of triglycerides (TG) in the pathogenesis of non-obese NAFLD. The findings suggest new treatments for NAFLD patients with normal BMI, as well as provide an early warning system for the understanding and prevention of NAFLD in non-obese patients.Methods: This cross-sectional study enrolled 159 959 Chinese subjects with BMI <24 kg/m2 and normal levels of low-density lipoprotein cholesterol (LDL-c). The average age was 40.21 ± 13.88 years, and males accounted for 45.7%. A total of 15 907 (9.94%) patients with NAFLD were diagnosed by ultrasonography. Biochemical indicators were measured using an automated analyzer (Abbott AxSYM). The BMI (kg/m2) was calculated from the weight (kg)/height in square meters (m2). The BMI quartile was used as the column-stratified variable to determine the baseline distribution and logistic regression analysis was used to assess the relationship between NAFLD and its risk factors, with multiple logistic regression used to assess the relationships between BMI or TG and NAFLD and multivariate linear regression used to analyze the association between BMI and TG, while mediation analysis was used to assess the mediation effect of TG.Results: After adjustment of all covariates, the odds ratios (ORs) were OR=1.788 (95%CI 1.749-1.829; P<0.00001) and OR=1.491 (95%CI 1.451-1.532; P<0.00001) for the association between BMI and TG with NAFLD incidence. The multivariate linear regression coefficient of BMI and TG was β=0.027 (95%CI 0.023-0.030; P<0.00001) Mediation analysis showed that BMI contributed to 10.81% of lean NAFLD with a mediation effect of 2.98%.Conclusion:In a Chinese population with BMI <24 kg/m2 and normal LDL-c levels, BMI and TG were found to be independent predictors of NAFLD. The direct effect of BMI on non-obese NAFLD was 10.41%. The TG level was found to partially mediate the association.

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“…And latest research revealed that LVMI increased progressively and LV diastolic function worsened with increasing number of steatosis scores in NAFLD patients. It also showed that liver steatosis, as identified by use of biochemical scores, predicted LV hypertrophy and diastolic dysfunction independently of blood pressure and obesity, and this association was independent of the HOMA-index for LV diastolic dysfunction [ 43 ]. Then there was a research showing that metabolic dysfunction-associated fatty liver disease patients had increased interventricular septum thickness, left ventricular posterior wall thickness, LVM and LVMI, and more patients with MAFLD had LV diastolic dysfunction compared to the normal group (60.8% vs 24.6%, p < 0.001).…”

Section: Discussionmentioning

confidence: 99%

Correlation between nonalcoholic fatty liver disease and left ventricular diastolic dysfunction in non-obese adults: a cross-sectional study

et al. 2023

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Background and aims Non-alcoholic fatty liver disease (NAFLD) is associated with a greater risk of developing cardiovascular disease and have adverse impacts on the cardiac structure and function. Little is known about the effect of non-obese NAFLD upon cardiac function. We aimed to compare the echocardiographic parameters of left ventricle (LV) between non-obese NAFLD group and control group, and explore the correlation of non-obese NAFLD with LV diastolic dysfunction. Methods and results In this cross-sectional study, 316 non-obese inpatients were enrolled, including 72 participants with NAFLD (non-obese NAFLD group) and 244 participants without NAFLD (control group). LV structural and functional indices of two groups were comparatively analyzed. LV diastolic disfunction was diagnosed and graded using the ratio of the peak velocity of the early filling (E) wave to the atrial contraction (A) wave and E value. Compared with control group, the non-obese NAFLD group had the lower E/A〔(0.80 ± 0.22) vs (0.88 ± 0.35), t = 2.528, p = 0.012〕and the smaller LV end-diastolic diameter〔(4.51 ± 0.42)cm vs (4.64 ± 0.43)cm, t = 2.182, p = 0.030〕. And the non-obese NAFLD group had a higher prevalence of E/A < 1 than control group (83.3% vs 68.9%, X2 = 5.802, p = 0.016) while two groups had similar proportions of LV diastolic dysfunction (58.3% vs 53.7%, X2 = 0.484, p = 0.487). Multivariate logistic regression analysis showed that non-obese NAFLD was associated with an increase in E/A < 1 (OR = 6.562, 95%CI 2.014, 21.373, p = 0.002). Conclusions Non-obese NAFLD was associated with decrease of E/A, while more research will be necessary to evaluate risk of non-obese NAFLD for LV diastolic dysfunction in future.

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Loss of immunity-related GTPase GM4951 leads to nonalcoholic fatty liver disease without obesity

Cited by 10 publications

References 46 publications

Metabolic effects of CCL5 deficiency in lean and obese mice

Metabolic effects of CCL5 deficiency in lean and obese mice

Triglycerides Mediate the Influence of Body Mass Index on Non-Alcoholic Fatty Liver Disease in a Non-Obese Chinese Population with Normal Low-Density Lipoprotein Cholesterol Levels

Correlation between nonalcoholic fatty liver disease and left ventricular diastolic dysfunction in non-obese adults: a cross-sectional study

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