The hepatic lipidome: From basic science to clinical translation

Hove, Marit ten; Pater, L. V.; Storm, Gert; Weiskirchen, Sabine; Weiskirchen, Ralf; Lammers, Twan; Bansal, Ruchi

doi:10.1016/j.addr.2020.06.027

Cited by 41 publications

(31 citation statements)

References 138 publications

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“…Different mouse strains exhibit variations in their liver lipidome and in their response to diets [ 77 ]. In addition, the lipidome can be affected by age, gender, and circadian rhythm [ 78 ]. Comparative studies are needed to identify the links between the tumor lipidome, genetic and environmental traits.…”

Section: Discussionmentioning

confidence: 99%

Accumulation of cholesterol, triglycerides and ceramides in hepatocellular carcinomas of diethylnitrosamine injected mice

et al. 2021

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Background Dysregulated lipid metabolism is critically involved in the development of hepatocellular carcinoma (HCC). The respective metabolic pathways affected in HCC can be identified using suitable experimental models. Mice injected with diethylnitrosamine (DEN) and fed a normal chow develop HCC. For the analysis of the pathophysiology of HCC in this model a comprehensive lipidomic analysis was performed. Methods Lipids were measured in tumor and non-tumorous tissues by direct flow injection analysis. Proteins with a role in lipid metabolism were analysed by immunoblot. Mann-Whitney U-test or paired Student´s t-test were used for data analysis. Results Intra-tumor lipid deposition is a characteristic of HCCs, and di- and triglycerides accumulated in the tumor tissues of the mice. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha, lipoprotein lipase and hepatic lipase protein were low in the tumors whereas proteins involved in de novo lipogenesis were not changed. Higher rates of de novo lipogenesis cause a shift towards saturated acyl chains, which did not occur in the murine HCC model. Besides, LDL-receptor protein and cholesteryl ester levels were higher in the murine HCC tissues. Ceramides are cytotoxic lipids and are low in human HCCs. Notably, ceramide levels increased in the murine tumors, and the simultaneous decline of sphingomyelins suggests that sphingomyelinases were involved herein. DEN is well described to induce the tumor suppressor protein p53 in the liver, and p53 was additionally upregulated in the tumors. Conclusions Ceramides mediate the anti-cancer effects of different chemotherapeutic drugs and restoration of ceramide levels was effective against HCC. High ceramide levels in the tumors makes the DEN injected mice an unsuitable model to study therapies targeting ceramide metabolism. This model is useful for investigating how tumors evade the cytotoxic effects of ceramides.

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Section: Discussionmentioning

confidence: 99%

Accumulation of cholesterol, triglycerides and ceramides in hepatocellular carcinomas of diethylnitrosamine injected mice

et al. 2021

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“…However, the liver not only controls cholesterol homeostasis, but communicates with other organs to coordinate overall lipid homeostasis in the body. Moreover, lipid metabolism is commonly disturbed in diabetic and obese patients during persistent and acute inflammation as well as in patients with chronic liver diseases [56][57][58][59][60][61][62], and often not directly related to defects in LDL-cholesterol uptake. Strikingly, increasing evidence points at additional roles for PCSK9 in the liver beyond cholesterol uptake via the LDL-R.…”

Section: Circulating Pcsk9 and Ldl-cholesterol Levels In Different Pa...mentioning

confidence: 99%

“…Excessive and continuously high intake of ethanol causes alcoholic liver disease, which ranges from alcoholic fatty liver to hepatitis, liver fibrosis and cirrhosis [105,106]. Fatty liver is an early stage and develops in ~60-90% of patients [58,107]. Disturbed hepatic lipid metabolism is a key feature of alcoholic liver disease, and liver steatosis is a risk factor for progressive liver damage [105].…”

Section: Pcsk9 and Alcoholic Liver Diseasementioning

confidence: 99%

Emerging Insights on the Diverse Roles of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Chronic Liver Diseases: Cholesterol Metabolism and Beyond

Grewal

Buechler

2022

IJMS

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Chronic liver diseases are commonly associated with dysregulated cholesterol metabolism. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease of the proprotein convertase family that is mainly synthetized and secreted by the liver, and represents one of the key regulators of circulating low-density lipoprotein (LDL) cholesterol levels. Its ability to bind and induce LDL-receptor degradation, in particular in the liver, increases circulating LDL-cholesterol levels in the blood. Hence, inhibition of PCSK9 has become a very potent tool for the treatment of hypercholesterolemia. Besides PCSK9 limiting entry of LDL-derived cholesterol, affecting multiple cholesterol-related functions in cells, more recent studies have associated PCSK9 with various other cellular processes, including inflammation, fatty acid metabolism, cancerogenesis and visceral adiposity. It is increasingly becoming evident that additional roles for PCSK9 beyond cholesterol homeostasis are crucial for liver physiology in health and disease, often contributing to pathophysiology. This review will summarize studies analyzing circulating and hepatic PCSK9 levels in patients with chronic liver diseases. The factors affecting PCSK9 levels in the circulation and in hepatocytes, clinically relevant studies and the pathophysiological role of PCSK9 in chronic liver injury are discussed.

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“…Liver tissues of healthy probands were not analysed for ethical issues and tissues of patients with non-viral HCC were not included. The main etiologies of non-viral HCC are alcohol abuse and NASH [ 4 , 60 ], and comparative lipidomic profiling of human liver tissues was not done so far [ 61 ]. Moreover, HCV genotype of half of the patients in our study was unknown.…”

Section: Discussionmentioning

confidence: 99%

Liver Lipids of Patients with Hepatitis B and C and Associated Hepatocellular Carcinoma

Haberl

Weiss

Peschel

et al. 2021

IJMS

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Hepatocellular carcinoma (HCC) still remains a difficult to cure malignancy. In recent years, the focus has shifted to lipid metabolism for the treatment of HCC. Very little is known about hepatitis B virus (HBV) and C virus (HCV)-related hepatic lipid disturbances in non-malignant and cancer tissues. The present study showed that triacylglycerol and cholesterol concentrations were similar in tumor adjacent HBV and HCV liver, and were not induced in the HCC tissues. Higher levels of free cholesterol, polyunsaturated phospholipids and diacylglycerol species were noted in non-tumorous HBV compared to HCV liver. Moreover, polyunsaturated phospholipids and diacylglycerols, and ceramides declined in tumors of HBV infected patients. All of these lipids remained unchanged in HCV-related HCC. In HCV tumors, polyunsaturated phosphatidylinositol levels were even induced. There were no associations of these lipid classes in non-tumor tissues with hepatic inflammation and fibrosis scores. Moreover, these lipids did not correlate with tumor grade or T-stage in HCC tissues. Lipid reprogramming of the three analysed HBV/HCV related tumors mostly resembled HBV-HCC. Indeed, lipid composition of non-tumorous HCV tissue, HCV tumors, HBV tumors and HBV/HCV tumors was highly similar. The tumor suppressor protein p53 regulates lipid metabolism. The p53 and p53S392 protein levels were induced in the tumors of HBV, HCV and double infected patients, and this was significant in HBV infection. Negative correlation of tumor p53 protein with free cholesterol indicates a role of p53 in cholesterol metabolism. In summary, the current study suggests that therapeutic strategies to target lipid metabolism in chronic viral hepatitis and associated cancers have to consider disease etiology.

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The hepatic lipidome: From basic science to clinical translation

Cited by 41 publications

References 138 publications

Accumulation of cholesterol, triglycerides and ceramides in hepatocellular carcinomas of diethylnitrosamine injected mice

Accumulation of cholesterol, triglycerides and ceramides in hepatocellular carcinomas of diethylnitrosamine injected mice

Emerging Insights on the Diverse Roles of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Chronic Liver Diseases: Cholesterol Metabolism and Beyond

Liver Lipids of Patients with Hepatitis B and C and Associated Hepatocellular Carcinoma

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