Inhibiting Ceramide Synthesis Attenuates Hepatic Steatosis and Fibrosis in Rats With Non-alcoholic Fatty Liver Disease

Jiang, Meng; Li, Chun; Liu, Qiaoshu; Wang, Aiming; Lei, Minxiang

doi:10.3389/fendo.2019.00665

Cited by 71 publications

(60 citation statements)

References 40 publications

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“…As noted above, a number of studies indicate that sphingolipids such as ceramides, which can induce each of these elements, including inflammation, oxidative stress, and mitochondrial dysfunction, to drive NASH (13). Myriocin, a potent inhibitor of SPT, inhibits NASH progression in rodents (43,44).…”

Section: Cers6 and Nashmentioning

confidence: 96%

Ceramide Synthases Are Attractive Drug Targets for Treating Metabolic Diseases

Raichur

2020

Front. Endocrinol.

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Ceramide synthases (CerS) are central enzymes required for the de-novo synthesis of ceramides and other sphingolipids. They catalyze the addition of different acyl-chains to a sphingoid base, and thus account for much of the rich diversity in the sphingolipid family. Recent studies have demonstrated that the acyl-chain is an important determinant of ceramide function, such that a small subset of ceramides (e.g., those containing the C16 or C18 acyl-chain) alter metabolism by inhibiting insulin signaling or inducing mitochondrial fragmentation. Herein I discuss the therapeutic potential of targeting certain ceramide synthase isoforms for the treatment of obesity, insulin resistance, steatohepatitis, and other metabolic disorders.

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Section: Cers6 and Nashmentioning

confidence: 96%

Ceramide Synthases Are Attractive Drug Targets for Treating Metabolic Diseases

Raichur

2020

Front. Endocrinol.

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“…Ceramide is a sphingolipid associated with oxidative stress and inflammation that is increased in the livers of NASH patients [ 64 ]. Inhibition of ceramide synthesis improves the steatosis and fibrosis in the livers of NAFLD rats [ 65 ]. The ceramide level is elevated in the brains from the LRRK2 knockout compared to wild-type mice [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

LRRK2 Regulates CPT1A to Promote β-Oxidation in HepG2 Cells

et al. 2020

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Leucine-rich repeat kinase 2 (LRRK2) is involved in lipid metabolism; however, the role of LRRK2 in lipid metabolism to affect non-alcoholic fatty liver disease (NAFLD) is still unclear. In the mouse model of NAFLD induced by a high-fat diet, we observed that LRRK2 was decreased in livers. In HepG2 cells, exposure to palmitic acid (PA) down-regulated LRRK2. Overexpression and knockdown of LRRK2 in HepG2 cells were performed to further investigate the roles of LRRK2 in lipid metabolism. Our results showed that β-oxidation in HepG2 cells was promoted by LRRK2 overexpression, whereas LRRK2 knockdown inhibited β-oxidation. The critical enzyme of β-oxidation, carnitine palmitoyltransferase 1A (CPT1A), was positively regulated by LRRK2. Our data suggested that the regulation of CPT1A by LRRK2 may be via the activation of AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor α (PPARα). The overexpression of LRRK2 reduced the concentration of a pro-inflammatory cytokine, tumor necrosis factor α (TNFα), induced by PA. The increase in β-oxidation may promote lipid catabolism to suppress inflammation induced by PA. These results indicated that LRRK2 participated in the regulation of β-oxidation and suggested that the decreased LRRK2 may promote inflammation by suppressing β-oxidation in the liver.

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“…A previous study reported that myriocin, an SPT inhibitor, inhibited JNK signaling in rats fed a high-fat diet. 35 Therefore, ceramide is a major modulator of JNK, rather than PKCε, for IRS1 regulation. Additionally, the amount of lipid droplets in the liver of the mice was reduced.…”

Section: Discussionmentioning

confidence: 99%

Hepatic Expression of the Serine Palmitoyltransferase Subunit Sptlc2 Reduces Lipid Droplets in the Liver by Activating VLDL Secretion

Kim

Park

et al. 2020

J Lipid Atheroscler

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Objective: Ceramide is a signaling molecule that contributes to insulin resistance and hepatosteatosis. In the present study, we activated de novo ceramide synthesis by inducing the hepatic expression of Sptlc2 to investigate the role of ceramide in glucose and lipid metabolism. Methods: We first constructed an adenovirus containing Sptlc2 (AdSptlc2), which encodes a major catalytic subunit of serine palmitoyltransferase (SPT). We then infected hepatocytes and mice fed a regular diet with AdSptlc2 to activate de novo ceramide biosynthesis. The liverspecific effects of ceramide biosynthesis on glucose and lipid metabolism were investigated by measuring changes in insulin signaling, lipid droplet formation, and very low-density lipoprotein (VLDL) secretion. Results: In HepG2 hepatocytes, adenoviral Sptlc2 expression inhibited insulin signaling and increased ceramide levels via activation of c-Jun N-terminal kinase and serine phosphorylation of insulin receptor substrate 1. In contrast, in mice, AdSptlc2 infection decreased plasma glucose levels by downregulating gluconeogenic genes and increased plasma triglyceride levels by increasing VLDL secretion. In mice infected with AdSptlc2, glucose intolerance and insulin sensitivity improved, while pyruvate utilization via gluconeogenesis decreased. Conclusion: Hepatic ceramide was found to modulate hepatosteatosis and the insulin response via increased VLDL secretion and inhibition of gluconeogenesis in vivo. Although inhibition of the insulin response was observed in vitro, the compensatory mechanism of relieving ceramide-induced stress and reducing ceramide levels resulted in improvements of glucose and lipid metabolic profiles in vivo. This discrepancy between in vitro and in vivo regulation mechanisms suggests that ceramide plays a role in non-alcoholic fatty liver disease and insulin resistance.

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Inhibiting Ceramide Synthesis Attenuates Hepatic Steatosis and Fibrosis in Rats With Non-alcoholic Fatty Liver Disease

Cited by 71 publications

References 40 publications

Ceramide Synthases Are Attractive Drug Targets for Treating Metabolic Diseases

Ceramide Synthases Are Attractive Drug Targets for Treating Metabolic Diseases

LRRK2 Regulates CPT1A to Promote β-Oxidation in HepG2 Cells

Hepatic Expression of the Serine Palmitoyltransferase Subunit Sptlc2 Reduces Lipid Droplets in the Liver by Activating VLDL Secretion

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