Triglyceride accumulation protects against fatty acid-induced lipotoxicity

Listenberger, Laura L.; Han, Xianlin; Lewis, Sarah; Cases, Sylvaine; Farese, Robert V.; Ory, Daniel S.; Schaffer, Jean E.

doi:10.1073/pnas.0630588100

Cited by 1,680 publications

(1,644 citation statements)

References 40 publications

Supporting

117

Mentioning

1,471

Contrasting

Unclassified

Order By: Relevance

“…The results obtained are in line with other investigations which demonstrated increase in the cell death, ceramide synthesis, and content in the liver and other cell types under the oversupply of saturated free fatty acids in the culture media (Merrill et al 1995;Wei et al 2006;Listenberger et al 2003;Blázquez et al 2000). Culturing of hepatocytes in the presence of α-tocopherol prevented the palmitate-induced cell damage.…”

Section: Discussionsupporting

confidence: 91%

Vitamin E prevents the age-dependent and palmitate-induced disturbances of sphingolipid turnover in liver cells

Babenko

Hassouneh

Kharchenko

et al. 2011

AGE

View full text Add to dashboard Cite

Sphingolipid turnover has been shown to be activated at old age and in response to various stress stimuli including oxidative stress. Reduction of vitamin E content in the liver under the pro-oxidant action is associated with enhanced sphingolipid turnover and ceramide accumulation in hepatocytes. In the present paper, the correction of sphingolipid metabolism in the liver cells of old rats and in the palmitate-treated young hepatocytes using α-tocopherol has been investigated. 3-and 24-month-old rats, [ 14 C] palmitic acid, [methyl− 14 C-choline]sphingomyelin (SM), and [ 14 C]serine were used. α-Tocopherol administration to old rats or addition to the culture medium of old liver slices or hepatocytes prevented age-dependent increase of ceramide synthesis and lipid accumulation, and increased SM content in liver tissue and cells. α-Tocopherol treatment of old cells decreased the neutral and acid sphingomyelinase (SMase) activities in hepatocytes and serine palmitoyl transferase activity in the liver cell microsomes. Effect of α-or γ-tocopherol, but not of δ-tocopherol, on the newly synthesized ceramide content in old cells was correlated with the action of inhibitor of serine palmitoyl transferase (SPT) activity (myriocin) and SMase inhibitors (glutathione, imipramine). Addition of α-tocopherol as well as myriocin to the culture medium of young hepatocytes, treated by palmitate, abolished ceramide accumulation and synthesis. The data obtained demonstrate that α-tocopherol normalized elevated ceramide content in the old liver cells via inhibition of acid and neutral SMase activities and lipid synthesis de novo. α-Tocopherol, reducing ceramide synthesis, prevented palmitate-induced aging-like ceramide accumulation in young liver cells.

show abstract

Section: Discussionsupporting

confidence: 91%

Vitamin E prevents the age-dependent and palmitate-induced disturbances of sphingolipid turnover in liver cells

Babenko

Hassouneh

Kharchenko

et al. 2011

AGE

View full text Add to dashboard Cite

show abstract

“…Several studies have demonstrated that the ability to synthesize TAG plays a critical role in the protection from palmitate‐induced lipotoxicity (Kamili et al ., 2015; Listenberger et al ., 2003; Przybytkowski et al ., 2007). For example, oleate supplementation promotes TAG synthesis in CHO cells and also prevents palmitate‐induced apoptosis in mouse embryonic fibroblasts but this protection was not seen in DGAT1 −/− mouse embryonic fibroblasts (Listenberger et al ., 2003).…”

Section: Discussionmentioning

confidence: 99%

“…For example, oleate supplementation promotes TAG synthesis in CHO cells and also prevents palmitate‐induced apoptosis in mouse embryonic fibroblasts but this protection was not seen in DGAT1 −/− mouse embryonic fibroblasts (Listenberger et al ., 2003). We demonstrate that pretreatment of MDA‐MB‐231 cells with oleate or FA mix protects from both palmitate‐induced and serum starvation‐induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…However, the nature of this effect is dependent on the chemical structure of FAs, the saturation level. Unsaturated FAs, including oleate and linoleate, support cell growth, whereas saturated FAs such as palmitate are toxic to cells (Hardy et al ., 2000; Listenberger et al ., 2003). Recently, we showed that coculturing BrCa cells with FA‐rich adipocytes increased TAG levels and promoted BrCa cell proliferation and migration, which were enhanced in the presence of obese adipocytes (Balaban et al ., 2017).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Heterogeneity of fatty acid metabolism in breast cancer cells underlies differential sensitivity to palmitate‐induced apoptosis

et al. 2018

View full text Add to dashboard Cite

Breast cancer (BrCa) metabolism is geared toward biomass synthesis and maintenance of reductive capacity. Changes in glucose and glutamine metabolism in BrCa have been widely reported, yet the contribution of fatty acids (FAs) in BrCa biology remains to be determined. We recently reported that adipocyte coculture alters MCF‐7 and MDA‐MB‐231 cell metabolism and promotes proliferation and migration. Since adipocytes are FA‐rich, and these FAs are transferred to BrCa cells, we sought to elucidate the FA metabolism of BrCa cells and their response to FA‐rich environments. MCF‐7 and MDA‐MB‐231 cells incubated in serum‐containing media supplemented with FAs accumulate extracellular FAs as intracellular triacylglycerols (TAG) in a dose‐dependent manner, with MDA‐MB‐231 cells accumulating more TAG. The differences in TAG levels were a consequence of distinct differences in intracellular partitioning of FAs, and not due to differences in the rate of FA uptake. Specifically, MCF‐7 cells preferentially partition FAs into mitochondrial oxidation, whereas MDA‐MB‐231 cells partition FAs into TAG synthesis. These differences in intracellular FA handling underpin differences in the sensitivity to palmitate‐induced lipotoxicity, with MDA‐MB‐231 cells being highly sensitive, whereas MCF‐7 cells are partially protected. The attenuation of palmitate‐induced lipotoxicity in MCF‐7 cells was reversed by inhibition of FA oxidation. Pretreatment of MDA‐MB‐231 cells with FAs increased TAG synthesis and reduced palmitate‐induced apoptosis. Our results provide novel insight into the potential influences of obesity on BrCa biology, highlighting distinct differences in FA metabolism in MCF‐7 and MDA‐MB‐231 cells and how lipid‐rich environments modulate these effects.

show abstract

“…36 A tempting interpretation is that when fatty acids are stored in triglycerides they are diverted from pathways that result in cellular damage. 37 Theoretically, such an effect could be explained by the accumulation of intermediate products along the chain of de novo lipogenesis, rather than by the reduction in the endproduct (here steatosis). In any case, the MCD model barely resembles human NASH, as only hepatic but not systemic IS is present.…”

Section: Efficacy Outcomesmentioning

confidence: 99%

Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

2010

View full text Add to dashboard Cite

Insulin sensitizers are attractive candidate therapies for nonalcoholic steatohepatitis mainly because of the strong association between this disease and insulin resistance. This review provides a critical overview of the mechanisms of action, clinical trial results, and safety issues of metformin and glitazones in nonalcoholic steatohepatitis. It also highlights methodological challenges for trial design and proposes endpoints for future proof of principle, registrational, and postmarketing trials. (HEPATOLOGY 2010;52:2206-2215 N onalcoholic steatohepatitis (NASH) is emerging as the next big therapeutic challenge in hepatology. 1 Currently the top cause of newly identified chronic liver diseases, NASH has potential for fibrosis, cirrhosis decompensation, and hepatocellular carcinoma. Not all individuals with metabolic risk factors will experience these adverse outcomes and identifying those at risk is critical. Prognostic markers for progression have mostly been derived from histological studies. Compared to steatosis alone or to steatosis and minimal inflammation, the coexistence of inflammation, cell injury (ballooning), and steatosis, a pathological aggregate labeled steatohepatitis, is associated with a significant increase in overall mortality and in liver-related mortality. The degree of inflammation is the best predictor of fibrosis progression, 2 a widely accepted surrogate for hard endpoints such as cirrhosis, endstage liver disease, and possibly hepatocellular carcinoma.Insulin resistance (IR) is consistently found in patients with NASH in both cross-sectional and longitudinal studies. Moreover, there is a stepwise increase in the severity of IR and its phenotypic complications (clustered as elements of the metabolic syndrome) between normal liver, isolated steatosis, and steatohepatitis that has prompted speculation that IR might contribute to liver damage. Logically, most therapeutic trials focused on insulin sensitizers (IS) as candidate therapies.The aim of this report is to critically review the results of trials of metformin and glitazones for NASH. We highlight methodological challenges for trial design and propose endpoints for future proof of principle, registrational, and postmarketing trials.

show abstract

Triglyceride accumulation protects against fatty acid-induced lipotoxicity

Cited by 1,680 publications

References 40 publications

Vitamin E prevents the age-dependent and palmitate-induced disturbances of sphingolipid turnover in liver cells

Vitamin E prevents the age-dependent and palmitate-induced disturbances of sphingolipid turnover in liver cells

Heterogeneity of fatty acid metabolism in breast cancer cells underlies differential sensitivity to palmitate‐induced apoptosis

Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

Contact Info

Product

Resources

About