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Molecular insight into palmitic acid-induced hepatocellular carcinoma cell death

ABSTRACT: The accumulation of lipid is a histological and biochemical hallmark of obesity-associated hepato-steatosis.Moreover, growing evidenceindicatesthathigher free fatty acids (FFAs) level in hepatocytes affects a myriad of biological processes leading to excessive metabolic imbalance, increased reactive oxygen species (ROS), deregulated autophagy, and impairment of mitochondrial and ER stress, that collectively drives cell death. Lipotoxicity and cell death mechanisms have been studied for many years. However, the molecular signals that link these two events during lipid stress remain poorly understood. From the very beginning, to systematically study hepato-lipotoxicity, HepG2 treated with PA providentially recapitulates the global lipotoxic responses, including insulin resistance to hepatocyte death. Therefore, using this cell-based model system, we pursued a comprehensive, differential quantitative approach where measurements of protein dynamics are analysed by mass spectrometry. Given that indispensable information, successive temporal phosphoproteomics dynamics are allowed us to in-depth analysis of lipotoxicity associated mechanistic network of cell death more precisely.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatocyte

SUBMITTER: TUSHAR KANTI MAITI

LAB HEAD: Dr. Tushar Kanti Maiti

PROVIDER: PXD029016 | Pride | 2022-07-16

REPOSITORIES: Pride

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Project description:Caloric Restriction in Leptin Deficiency Worsens Myocardial Steatosis: Failure to Upregulate PPAR gamma and Thermogenic Glyecrolipid/Fatty Acid Cycling Growing evidence supports an anti-lipotoxic role for leptin in preventing inappropriate peripheral tissue lipid deposition. Obese, leptin deficient ob/ob mice develop left ventricular (LV) hypertrophy and myocardial steatosis with increased apoptosis and decreased longevity. Here we investigated the cardiac effects of caloric restriction in leptin deficiency. Echocardiography was performed on C57Bl/6 wild-type mice (WT) and 7-month-old ob/ob mice fed ad lib, leptin-repleted (LR-ob/ob), or calorie-restricted (CR-ob/ob) for four weeks. Ventricular tissue was examined by electron microscopy (EM), mitochondrial coupling assay, and microarray expression profiling. LR and CR-ob/ob mice showed decreased body weight, heart weight, and LV wall thickness compared to ad lib ob/ob mice. LV fractional shortening was decreased in ad lib ob/ob mice, but restored to WT levels in LR and CR groups. However, EM revealed severe cardiac steatosis in the CR-ob/ob group compared to only moderate steatosis in ad lib ob/ob . Despite marked cardiac steatosis, CR (like LR) restored mitochondrial coupling to WT levels. CR up-regulated genes associated with oxidative stress and cell death, changes suggestive of cardiac lipotoxicity. LR, but not CR was shown to induce core genes involved in glycerolipid/free fatty acid cycling, a highly thermogenic pathway that can reduce intracellular lipid stores. LR, but not CR up-regulated and restored PGC1 and PPARto wild type levels; CR paradoxically further suppressed cardiac PPAR. Thus, leptin is essential in protecting the heart from lipotoxicity, and the inability to up-regulate the thermogenic glycerolipid/free fatty acid cycling pathway may impair the response of leptin deficient animals to the lipotoxic stress of calorie restriction. 6 month aged ob/ob mice were either leptin repleted with osmotic mini-pumps, calorie restricted to match the caloric intake of the leptin repleted mice, or fed ad lib for one month. 6-8 month C57Bl/6J mice were aged to serve as controls.

			Action	DRS
	F000045.dat	Other
	F000045_BR1_6HR.csv	Csv
	F000046.dat	Other
	F000046_BR1_0HR.csv	Csv
	F000047.dat	Other

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Molecular insight into palmitic acid-induced hepatocellular carcinoma cell death

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