Plasma Fatty Acid Composition Is Associated with Histological Findings of Nonalcoholic Steatohepatitis

Miyake, Teruki; Furukawa, Shinya; Matsuura, Bunzo; Yoshida, Osamu; Miyazaki, M; Shiomi, Akihito; Kanzaki, Sayaka; Nakaguchi, Hironobu; Sunago, Kotaro; Nakamura, Yoshiko; Imai, Yusuke; Watanabe, Takao; Yamamoto, Yasunori; Terada, Yoshio; Hirooka, Masashi; Kumagi, Teru; Abe, Masanori; Hiasa, Yoichi

doi:10.3390/biomedicines10102540

Cited by 10 publications

(5 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lauric acid has been reported to participate in multiple metabolic and cardiovascular diseases (Kamoshita et al, 2022 ; Miyake et al, 2022 ; Saraswathi et al, 2020 ). It should be noted that coconut oil, which contains 50% lauric acid as the primary fatty acid, induces IR in the liver but not in skeletal muscle and adipose tissue (Turner et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, heart failure patients with MetS displayed a higher proportion of lauric acid than heart failure patients without MetS (Lee et al, 2012 ). In a nonalcoholic fatty liver disease (NAFLD) cohort, higher lauric acid was significantly associated with a high NAFLD activity score in analyses adjusted for the same factors and fibrosis stage(Miyake et al, 2022 ). In our study, lauric acid was highly accumulated in the livers of Acsm3 knockout mice, playing a crucial role in causing the MetS phenotype.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Liver ACSM3 deficiency mediates metabolic syndrome via a lauric acid-HNF4α-p38 MAPK axis

Xiao,

Li,

Cui

et al. 2024

EMBO J

View full text Add to dashboard Cite

Metabolic syndrome combines major risk factors for cardiovascular disease, making deeper insight into its pathogenesis important. We here explore the mechanistic basis of metabolic syndrome by recruiting an essential patient cohort and performing extensive gene expression profiling. The mitochondrial fatty acid metabolism enzyme acyl-CoA synthetase medium-chain family member 3 (ACSM3) was identified to be significantly lower expressed in the peripheral blood of metabolic syndrome patients. In line, hepatic ACSM3 expression was decreased in mice with metabolic syndrome. Furthermore, Acsm3 knockout mice showed glucose and lipid metabolic abnormalities, and hepatic accumulation of the ACSM3 fatty acid substrate lauric acid. Acsm3 depletion markedly decreased mitochondrial function and stimulated signaling via the p38 MAPK pathway cascade. Consistently, Acsm3 knockout mouse exhibited abnormal mitochondrial morphology, decreased ATP contents, and enhanced ROS levels in their livers. Mechanistically, Acsm3 deficiency, and lauric acid accumulation activated nuclear receptor Hnf4α-p38 MAPK signaling. In line, the p38 inhibitor Adezmapimod effectively rescued the Acsm3 depletion phenotype. Together, these findings show that disease-associated loss of ACSM3 facilitates mitochondrial dysfunction via a lauric acid-HNF4a-p38 MAPK axis, suggesting a novel therapeutic vulnerability in systemic metabolic dysfunction.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Liver ACSM3 deficiency mediates metabolic syndrome via a lauric acid-HNF4α-p38 MAPK axis

Xiao,

Li,

Cui

et al. 2024

EMBO J

View full text Add to dashboard Cite

show abstract

“…The fibrosis stage was defined as previously described [19,20]: stage 0, absence of fibrosis; stage 1a, delicate perisinusoidal fibrosis; stage 1b, dense perisinusoidal fibrosis; stage 1c, portal-only fibrosis without perisinusoidal fibrosis; stage 2, combined perisinusoidal and portal/periportal fibrosis; stage 3, bridging fibrosis; and stage 4, cirrhosis. Advanced fibrosis and high NAS were defined as stages 3-4 and 5-8, respectively [21,22].…”

Section: Measurements and Evaluationsmentioning

confidence: 99%

Glycemic Control Is Associated with Histological Findings of Nonalcoholic Fatty Liver Disease

Miyake,

Furukawa,

Matsuura

et al. 2024

Diabetes Metab J

Self Cite

View full text Add to dashboard Cite

Background: Poor lifestyle habits may worsen nonalcoholic fatty liver disease (NAFLD), with progression to nonalcoholic steatohepatitis (NASH) and cirrhosis. This study investigated the association between glycemic control status and hepatic histological findings to elucidate the effect of glycemic control on NAFLD.Methods: This observational study included 331 patients diagnosed with NAFLD by liver biopsy. Effects of the glycemic control status on histological findings of NAFLD were evaluated by comparing the following four glycemic status groups defined by the glycosylated hemoglobin (HbA1c) level at the time of NAFLD diagnosis: ≤5.4%, 5.5%–6.4%, 6.5%–7.4%, and ≥7.5%.Results: Compared with the lowest HbA1c group (≤5.4%), the higher HbA1c groups (5.5%–6.4%, 6.5%–7.4%, and ≥7.5%) were associated with advanced liver fibrosis and high NAFLD activity score (NAS). On multivariate analysis, an HbA1c level of 6.5%– 7.4% group was significantly associated with advanced fibrosis compared with the lowest HbA1c group after adjusting for age, sex, hemoglobin, alanine aminotransferase, and creatinine levels. When further controlling for body mass index and uric acid, total cholesterol, and triglyceride levels, the higher HbA1c groups were significantly associated with advanced fibrosis compared with the lowest HbA1c group. On the other hand, compared with the lowest HbA1c group, the higher HbA1c groups were also associated with a high NAS in both multivariate analyses.Conclusion: Glycemic control is associated with NAFLD exacerbation, with even a mild deterioration in glycemic control, especially a HbA1c level of 6.5%–7.4%, contributing to NAFLD progression.

show abstract

“…Moreover, several clinical studies report that as NAFLD severity progresses, i.e., NAFLD transition to NASH and cirrhosis, hepatic EFAs and their products decrease [37][38][39][40][42][43][44][45]47]. A recent report indicates that key ω6 and ω3 C 18-22 PUFA are low, while mead acid (20:3, ω9) is elevated in plasma of humans with biopsy-confirmed NASH [68]. Explanations for these observations are based on the low levels or an imbalance of EFAs in western-like diets [26,69] (S1A Fig) and the impairment in hepatic desaturation and/or elongation pathways required to convert the C 18 EFA precursors to C 20-22 ω3 and ω6 PUFA products [38,70].…”

Section: Plos Onementioning

confidence: 99%

Time course of western diet (WD) induced nonalcoholic steatohepatitis (NASH) in female and male Ldlr-/- mice

Spooner,

Garcia-Jaramillo,

Apperson

et al. 2023

PLoS ONE

View full text Add to dashboard Cite

Background Nonalcoholic fatty liver disease (NAFLD) is a global health problem. Identification of factors contributing to the onset and progression of NAFLD have the potential to direct novel strategies to combat NAFLD. Methods We examined the time course of western diet (WD)-induced NAFLD and its progression to nonalcoholic steatohepatitis (NASH) in age-matched female and male Ldlr-/- mice, with time-points at 1, 4, 8, 20 and 40 weeks on the WD. Controls included Ldlr-/- mice maintained on a purified low-fat diet (LFD) for 1 and 40 weeks. The approach included quantitation of anthropometric, plasma and liver markers of disease, plus hepatic histology, lipids, oxylipins, gene expression and selected metabolites. Results One week of feeding the WD caused a significant reduction in hepatic essential fatty acids (EFAs: 18:2, ω6, 18:3, ω3) which preceded the decline in many C20-22 ω3 and ω6 polyunsaturated fatty acids (PUFA) and PUFA-derived oxylipins after 4 weeks on the WD. In addition, expression of hepatic inflammation markers (CD40, CD44, Mcp1, Nlrp3, TLR2, TLR4, Trem2) increased significantly in both female & male mice after one week on the WD. These markers continued to increase over the 40-week WD feeding study. WD effects on hepatic EFA and inflammation preceded all significant WD-induced changes in body weight, insulin resistance (HOMA-IR), oxidative stress status (GSH/GSSG ratio) and histological and gene expression markers of macrosteatosis, extracellular matrix remodeling and fibrosis. Conclusions Our findings establish that feeding Ldlr-/- mice the WD rapidly lowered hepatic EFAs and induced key inflammatory markers linked to NASH. Since EFAs have an established role in inflammation and hepatic inflammation plays a major role in NASH, we suggest that early clinical assessment of EFA status and correcting EFA deficiencies may be useful in reducing NASH severity.

show abstract

Plasma Fatty Acid Composition Is Associated with Histological Findings of Nonalcoholic Steatohepatitis

Cited by 10 publications

References 30 publications

Liver ACSM3 deficiency mediates metabolic syndrome via a lauric acid-HNF4α-p38 MAPK axis

Liver ACSM3 deficiency mediates metabolic syndrome via a lauric acid-HNF4α-p38 MAPK axis

Glycemic Control Is Associated with Histological Findings of Nonalcoholic Fatty Liver Disease

Time course of western diet (WD) induced nonalcoholic steatohepatitis (NASH) in female and male Ldlr-/- mice

Contact Info

Product

Resources

About