Microvesicular Steatosis Induced by a Short Chain Fatty Acid: Effects on Mitochondrial Function and Correlation with Gene Expression

Jolly, Robert A.; Ciurlionis, Rita; Morfitt, David C.; Helgren, Mary C.; Patterson, Reid; Ulrich, Roger G.; Waring, Jeffrey F.

doi:10.1080/01926230490451699

Cited by 24 publications

(17 citation statements)

References 24 publications

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“…Microscopic analysis of liver slices revealed a mixed micro/macrovesicular accumulation of lipid droplets, also called micro/macrovesicular steatosis (data not shown). This observation of microvesicular steatosis seems to be in agreement with the recent finding with cyclopropane carboxylic acid (CPCA), another ␤-oxidation inhibitor, in rats (38). Although one might expect to observe increased liver mRNA levels of TG-synthesizing enzymes such as DGAT1, this was not observed in our experimental setting.…”

Section: Discussionsupporting

confidence: 78%

Acute inhibition of hepatic β-oxidation in APOE*3Leiden mice does not affect hepatic VLDL secretion or insulin sensitivity

Duivenvoorden

Teusink

Rensen

et al. 2005

Journal of Lipid Research

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Hepatic VLDL and glucose production is enhanced in type 2 diabetes and associated with hepatic steatosis. Whether the derangements in hepatic metabolism are attributable to steatosis or to the increased availability of FA metabolites is not known. We used methyl palmoxirate (MP), an inhibitor of carnitine palmitoyl transferase I, to acutely inhibit hepatic FA oxidation and investigated whether the FAs were rerouted into VLDL secretion and whether this would affect hepatic glucose production. After an overnight fast, male APOE3*Leiden transgenic mice received an oral dose of 10 mg/kg MP. Administration of MP led to an 83% reduction in plasma ␤ -hydroxybutyrate (ketone body) levels compared with vehicle-treated mice (0.47 ؎ 0.07 vs. 2.81 ؎ 0.16 mmol/l, respectively; P Ͻ 0.01), indicative of impaired ketogenesis. Plasma FFA levels were increased by 32% and cholesterol and insulin levels were decreased by 17% and 50%, respectively, in MP-treated mice compared with controls. MP treatment led to a 30% increase in liver triglyceride (TG) content. Surprisingly, no effect on hepatic VLDL-TG production was observed between the groups at 8 h after MP administration. In addition, the capacity of insulin to suppress endogenous glucose production was unaffected in MP-treated mice compared with controls.In conclusion, acute inhibition of FA oxidation increases hepatic lipid content but does not stimulate hepatic VLDL secretion or reduce insulin sensitivity. Hepatic VLDL-triglyceride (TG) secretion is an important determinant of plasma lipid levels. The rate of VLDL secretion is generally believed to be substrate-driven (i.e., the hepatic content of TG and FA determines VLDL assembly and the rate of VLDL secretion) (1-3). Indeed, addition of FA to hepatocytes in vitro leads to increased hepatic TG and eventually to enhanced VLDL secretion (4). However, the hypothesis that VLDL secretion is substratedriven in vivo has not been proven.Hepatic TG content is the result of uptake and synthesis on the one hand and ␤ -oxidation and VLDL-TG secretion on the other. The importance of ␤ -oxidation is illustrated by the severe phenotype of humans and mice with impaired ␤ -oxidation. Deficiency in hepatic ␤ -oxidation enzymes results in severe plasma hypoketosis and fatty liver (5, 6). In ␤ -oxidation, the rate-limiting enzyme is carnitine palmitoyl transferase 1 (CPT1), which couples long-chain FAs to carnitine for transportation into the mitochondria (7,8). Methyl palmoxirate (MP) is a specific and irreversible inhibitor of CPT1 and thereby inhibits ␤ -oxidation (9, 10).In this study, we tested the effect of acute inhibition of ␤ -oxidation in vivo by MP on hepatic VLDL production in fasted hyperlipidemic APOE3*Leiden transgenic mice.Abbreviations: acc1 , acetyl-coenzyme A carboxylase 1; apoB, apolipoprotein B; CPT1, carnitine palmitoyl transferase 1; dgat , acyl:diacylglycerol transferase; fas , fatty acid synthase; ␤ -HB, ␤ -hydroxybutyrate; hmgs , 3-hydroxy-3-methylglutaryl-coenzyme A synthase; mcad , mediumchain acyl coenzyme...

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Section: Discussionsupporting

confidence: 78%

Acute inhibition of hepatic β-oxidation in APOE*3Leiden mice does not affect hepatic VLDL secretion or insulin sensitivity

Duivenvoorden

Teusink

Rensen

et al. 2005

Journal of Lipid Research

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“…With nonalcoholic fatty liver disease (NAFLD), macrovesicular steatosis, but rarely microvesicular or a mix of micro‐ and macro‐vesicular steatosis, develops (33, 34). Microvesicular steatosis is mostly associated with mitochondria dysfunction (35, 36). Portocentral gradient with increasing macro‐vesicular steatosis from the central vein toward the portal region was evident in HSD17B13KO mouse liver.…”

Section: Discussionmentioning

confidence: 99%

Hydroxysteroid (17β) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice

Adam

Heikelä

Sobolewski³

et al. 2018

FASEB j.

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Hydroxysteroid (17β) dehydrogenases (HSD17Bs) form an enzyme family characterized by their ability to catalyze reactions in steroid and lipid metabolism. In the present study, we characterized the phenotype of HSD17B13-knockout (HSD17B13KO) mice deficient in Hsd17b13. In these studies, hepatic steatosis was detected in HSD17B13KO male mice, indicated by histologic analysis and by the increased triglyceride concentration in the liver, whereas reproductive performance and serum steroid concentrations were normal in HSD17B13KO mice. In line with these changes, the expression of key proteins in fatty acid synthesis, such as FAS, acetyl-CoA carboxylase 1, and SCD1, was increased in the HSD17B13KO liver. Furthermore, the knockout liver showed an increase in 2 acylcarnitines, suggesting impaired mitochondrial β-oxidation in the presence of unaltered malonyl CoA and AMPK expression. The glucose tolerance did not differ between wild-type and HSD17B13KO mice in the presence of lower levels of glucose 6-phosphatase in HSD17B13KO liver compared with wild-type liver. Furthermore, microgranulomas and increased portal inflammation together with up-regulation of immune response genes were observed in HSD17B13KO mice. Our data indicate that disruption of Hsd17b13 impairs hepatic-lipid metabolism in mice, resulting in liver steatosis and inflammation, but the enzyme does not play a major role in the regulation of reproductive functions.-Adam, M., Heikelä, H., Sobolewski, C., Portius, D., Mäki-Jouppila, J., Mehmood, A., Adhikari, P., Esposito, I., Elo, L. L., Zhang, F.-P., Ruohonen, S. T., Strauss, L., Foti, M., Poutanen, M. Hydroxysteroid (17β) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice.

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“…In contrast, micro-vesicular steatosis is generally a more severe form of steatosis and is seen in a variety of conditions such as toxicity of several medications, defect in beta-oxidation of fatty acids, Reye's syndrome but also in alcoholism. Although the pathogenesis is not clearly understood, an impaired mitochondrial beta-oxidation seems to be an underlying factor [34][35][36].…”

Section: Introductionmentioning

confidence: 99%

Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance

Schwenzer

Springer

Schraml

et al. 2009

Journal of Hepatology

692

562

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Microvesicular Steatosis Induced by a Short Chain Fatty Acid: Effects on Mitochondrial Function and Correlation with Gene Expression

Cited by 24 publications

References 24 publications

Acute inhibition of hepatic β-oxidation in APOE*3Leiden mice does not affect hepatic VLDL secretion or insulin sensitivity

Acute inhibition of hepatic β-oxidation in APOE*3Leiden mice does not affect hepatic VLDL secretion or insulin sensitivity

Hydroxysteroid (17β) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice

Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance

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