INVESTIGADORES
PIROLA Carlos Jose
artículos
Título:
Metabolic Profiling reveals that pnpla3 induces widespread effects on metabolism beyond Triacylglycerol remodeling in huh-7 hepatoma cells
Autor/es:
MIN, HK; SOOKOIAN S,; PIROLA CJ; CHENG J; MIRSHAHI F; SANYAL AJ
Revista:
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Editorial:
AMER PHYSIOLOGICAL SOC
Referencias:
Lugar: Bethesda; Año: 2014 vol. 307 p. 66 - 76
ISSN:
0193-1857
Resumen:
PNPLA3 was recently
associated with the susceptibility to nonalcoholic fatty liver disease, a
common cause of chronic liver disease characterized by abnormal
triglyceride accumulation. Although it is established that PNPLA3PNPLA3 was recently
associated with the susceptibility to nonalcoholic fatty liver disease, a
common cause of chronic liver disease characterized by abnormal
triglyceride accumulation. Although it is established that PNPLA3PNPLA3
has both triacylglycerol lipase and acylglycerol O-acyltransferase
activities, is still unknown whether the gene has any additional role
in the modulation of the human liver metabolome. To uncover the
functional role of PNPLA3 on liver metabolism, we performed
high-throughput metabolic profiling of PNPLA3 siRNA-silencing
and overexpression of wild-type and mutant Ile148Met variants
(isoleucine/methionine substitution at codon 148) in Huh-7 cells.
Metabolomic analysis was performed by using GC/MS and LC/MS
platforms. Silencing of PNPLA3 was associated with a global
perturbation of Huh-7 hepatoma cells that resembled a catabolic
response associated with protein breakdown. A significant decrease
in amino- and -glutamyl-amino acids and dipeptides and a significant
increase in cysteine sulfinic acid, myo-inositol, lysolipids,
sphingolipids, and polyunsaturated fatty acids were observed.
Overexpression of the PNPLA3 Met148 variant mirrored many of
the metabolic changes observed during gene silencing, but in the
opposite direction. These findings were replicated by the exploration
of canonical pathways associated with PNPLA3 silencing and
Met148 overexpression. Overexpression of the PNPLA3 Met148
variant was associated with a 1.75-fold increase in lactic acid,
suggesting a shift to anaerobic metabolism and mitochondrial
dysfunction. Together, these results suggest a critical role ofO-acyltransferase
activities, is still unknown whether the gene has any additional role
in the modulation of the human liver metabolome. To uncover the
functional role of PNPLA3 on liver metabolism, we performed
high-throughput metabolic profiling of PNPLA3 siRNA-silencing
and overexpression of wild-type and mutant Ile148Met variants
(isoleucine/methionine substitution at codon 148) in Huh-7 cells.
Metabolomic analysis was performed by using GC/MS and LC/MS
platforms. Silencing of PNPLA3 was associated with a global
perturbation of Huh-7 hepatoma cells that resembled a catabolic
response associated with protein breakdown. A significant decrease
in amino- and -glutamyl-amino acids and dipeptides and a significant
increase in cysteine sulfinic acid, myo-inositol, lysolipids,
sphingolipids, and polyunsaturated fatty acids were observed.
Overexpression of the PNPLA3 Met148 variant mirrored many of
the metabolic changes observed during gene silencing, but in the
opposite direction. These findings were replicated by the exploration
of canonical pathways associated with PNPLA3 silencing and
Met148 overexpression. Overexpression of the PNPLA3 Met148
variant was associated with a 1.75-fold increase in lactic acid,
suggesting a shift to anaerobic metabolism and mitochondrial
dysfunction. Together, these results suggest a critical role ofPNPLA3 on liver metabolism, we performed
high-throughput metabolic profiling of PNPLA3 siRNA-silencing
and overexpression of wild-type and mutant Ile148Met variants
(isoleucine/methionine substitution at codon 148) in Huh-7 cells.
Metabolomic analysis was performed by using GC/MS and LC/MS
platforms. Silencing of PNPLA3 was associated with a global
perturbation of Huh-7 hepatoma cells that resembled a catabolic
response associated with protein breakdown. A significant decrease
in amino- and -glutamyl-amino acids and dipeptides and a significant
increase in cysteine sulfinic acid, myo-inositol, lysolipids,
sphingolipids, and polyunsaturated fatty acids were observed.
Overexpression of the PNPLA3 Met148 variant mirrored many of
the metabolic changes observed during gene silencing, but in the
opposite direction. These findings were replicated by the exploration
of canonical pathways associated with PNPLA3 silencing and
Met148 overexpression. Overexpression of the PNPLA3 Met148
variant was associated with a 1.75-fold increase in lactic acid,
suggesting a shift to anaerobic metabolism and mitochondrial
dysfunction. Together, these results suggest a critical role ofPNPLA3 siRNA-silencing
and overexpression of wild-type and mutant Ile148Met variants
(isoleucine/methionine substitution at codon 148) in Huh-7 cells.
Metabolomic analysis was performed by using GC/MS and LC/MS
platforms. Silencing of PNPLA3 was associated with a global
perturbation of Huh-7 hepatoma cells that resembled a catabolic
response associated with protein breakdown. A significant decrease
in amino- and -glutamyl-amino acids and dipeptides and a significant
increase in cysteine sulfinic acid, myo-inositol, lysolipids,
sphingolipids, and polyunsaturated fatty acids were observed.
Overexpression of the PNPLA3 Met148 variant mirrored many of
the metabolic changes observed during gene silencing, but in the
opposite direction. These findings were replicated by the exploration
of canonical pathways associated with PNPLA3 silencing and
Met148 overexpression. Overexpression of the PNPLA3 Met148
variant was associated with a 1.75-fold increase in lactic acid,
suggesting a shift to anaerobic metabolism and mitochondrial
dysfunction. Together, these results suggest a critical role ofPNPLA3 was associated with a global
perturbation of Huh-7 hepatoma cells that resembled a catabolic
response associated with protein breakdown. A significant decrease
in amino- and -glutamyl-amino acids and dipeptides and a significant
increase in cysteine sulfinic acid, myo-inositol, lysolipids,
sphingolipids, and polyunsaturated fatty acids were observed.
Overexpression of the PNPLA3 Met148 variant mirrored many of
the metabolic changes observed during gene silencing, but in the
opposite direction. These findings were replicated by the exploration
of canonical pathways associated with PNPLA3 silencing and
Met148 overexpression. Overexpression of the PNPLA3 Met148
variant was associated with a 1.75-fold increase in lactic acid,
suggesting a shift to anaerobic metabolism and mitochondrial
dysfunction. Together, these results suggest a critical role ofmyo-inositol, lysolipids,
sphingolipids, and polyunsaturated fatty acids were observed.
Overexpression of the PNPLA3 Met148 variant mirrored many of
the metabolic changes observed during gene silencing, but in the
opposite direction. These findings were replicated by the exploration
of canonical pathways associated with PNPLA3 silencing and
Met148 overexpression. Overexpression of the PNPLA3 Met148
variant was associated with a 1.75-fold increase in lactic acid,
suggesting a shift to anaerobic metabolism and mitochondrial
dysfunction. Together, these results suggest a critical role ofPNPLA3 Met148 variant mirrored many of
the metabolic changes observed during gene silencing, but in the
opposite direction. These findings were replicated by the exploration
of canonical pathways associated with PNPLA3 silencing and
Met148 overexpression. Overexpression of the PNPLA3 Met148
variant was associated with a 1.75-fold increase in lactic acid,
suggesting a shift to anaerobic metabolism and mitochondrial
dysfunction. Together, these results suggest a critical role ofPNPLA3 silencing and
Met148 overexpression. Overexpression of the PNPLA3 Met148
variant was associated with a 1.75-fold increase in lactic acid,
suggesting a shift to anaerobic metabolism and mitochondrial
dysfunction. Together, these results suggest a critical role ofPNPLA3 Met148
variant was associated with a 1.75-fold increase in lactic acid,
suggesting a shift to anaerobic metabolism and mitochondrial
dysfunction. Together, these results suggest a critical role of
PNPLA3 in the modulation of liver metabolism beyond its classical
participation in triacylglycerol remodeling.in the modulation of liver metabolism beyond its classical
participation in triacylglycerol remodeling.