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

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.

(A) Timeline of Acsm3 KO and control mice fed with an FF diet.(B) The average daily food intake of Acsm3 KO and control mice for 5 consecutive days (n = 6 biologically independent samples in each group).Values were represented as the mean ± SD.Statistics were performed using Student's t test.(C, D) The fasting Glu (mmol/L), fasting Ins (μU/mL) of Acsm3 KO and control mice.(E) The contents of hepatic TC (mmol/gprot), TG (mmol/gprot), and NEFA (μmol/g) in Acsm3 KO and control mice (n = 6 biologically independent samples in each group).Values were represented as the mean ± SD.Statistics were performed using Student's t test.

Xiao Xiao et al
The EMBO Journal (A) Timeline of shAcsm3 mice (Adeno-associated virus 8 (AAV8) injection induced liver-specific knockdown of Acsm3 in mice) and shControl mice under ND.(B) Western blot showing the relative expression of Acsm3 in the liver and kidney of shAcsm3 and shControl mice.(C) The body weights (g), liver weights (g), and liver weight/body weight of shAcsm3 and shControl mice (n = 6 biologically independent samples in each group).Values were represented as the mean ± SD.Statistics were performed using Student's t test.(D, E) GTT, ITT, and respective AUC of shAcsm3 and shControl mice (n = 6 biologically independent samples in each group).Values were represented as the mean ± SD.Statistics were performed using Student's t test.P values were denoted by asterisks: *P < 0.05.(F, G) The fasting Glu (mmol/L), fasting Ins (μU/mL), and HOMA-IR indexes of shAcsm3 and shControl mice (n = 6 biologically independent samples in each group).HOMA-IR = fasting Glu (mmol/L) × fasting Ins (μU/mL)/22.5.Values were represented as the mean ± SD.Statistics were performed using Student's t test.(H) The contents (IU/mL) of serum ALT and AST in shAcsm3 and shControl mice (n = 6 biologically independent samples in each group).Values were represented as the mean ± SD.Statistics were performed using Student's t test.(I) The contents of hepatic TC (mmol/gprot), TG ((mmol/gprot)), and NEFA (μmol/g) in shAcsm3 and shControl mice (n = 6 biologically independent samples in each group).Values were represented as the mean ± SD.Statistics were performed using Student's t test.(J) The contents (mmol/L) of serum TC, TG, NEFA, HDL-C, and LDL-C in shAcsm3 and shControl mice (n = 6 biologically independent samples in each group).Values were represented as the mean ± SD.Statistics were performed using Student's t test.

Xiao Xiao et al
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The The EMBO Journal © The Author(s) (A) Timeline of shAcsm3 mice and shControl mice fed with an FF diet.(B) Western blot showing the relative expression of Acsm3 in the liver and kidney of shAcsm3 and shControl mice.(C) The body weights (g), liver weights (g), and liver weight/body weight of shAcsm3 and shControl mice (n = 6 biologically independent samples in each group).Values were represented as the mean ± SD.Statistics were performed using Student's t test.(D, E) GTT, ITT, and respective AUC of shAcsm3 and shControl mice (n = 6 biologically independent samples in each group).Values were represented as the mean ± SD.Statistics were performed using Student's t test.P values were denoted by asterisks: **P < 0.01.(F, G) The fasting Glu (mmol/L), fasting Ins (μU/mL), and HOMA-IR indexes of shAcsm3 and shControl mice (n = 6 biologically independent samples in each group).HOMA-IR = fasting Glu (mmol/L) × fasting Ins (μU/mL)/22.5.Values were represented as the mean ± SD.Statistics were performed using Student's t test.(H) The contents (IU/mL) of serum ALT and AST in shAcsm3 and shControl mice (n = 6 biologically independent samples in each group).Values were represented as the mean ± SD.Statistics were performed using Student's t test.(I) The contents of hepatic TC (mmol/gprot), TG ((mmol/gprot)), and NEFA (μmol/g) in shAcsm3 and shControl mice (n = 6 biologically independent samples in each group).Values were represented as the mean ± SD.Statistics were performed using Student's t test.(J) The contents (mmol/L) of serum TC, TG, NEFA, HDL-C, and LDL-C in shAcsm3 and shControl mice (n = 6 biologically independent samples in each group).Values were represented as the mean ± SD.Statistics were performed using Student's t test.

Xiao Xiao et al
The EMBO Journal © The Author(s) The EMBO Journal

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Figure EV5.The body weights (g), liver weights (g), and liver weight/body weight of Acsm3 KO and control mice treated with adezmapimod or not.
Values were represented as the mean ± SD (n = 6 biologically independent samples in each group).Statistics were performed using Student's t test.
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