Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease

Kohjima, Motoyuki; Enjoji, Munechika; Higuchi, Nobito; Kato, Masaki; Kotoh, Kazuhiro; Yoshimoto, Tsuyoshi; Fujino, Tatsuya; Yada, Masayoshi; Yada, Ryoko; Harada, Naohiko; Takayanagi, Ryoichi; Nakamuta, Makoto

doi:10.3892/ijmm.20.3.351

Cited by 313 publications

(343 citation statements)

References 30 publications

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“…In an experiment using rats fed a highfat diet, the mRNA expression of lipogenic enzymes including hepatic FASN was down-regulated by dietary levan, while hepatic PPARα mRNA expression was up-regulated by dietary levan (7). It was also reported that the gene expression of lipogenic enzymes including FASN was increased while that of PPARα was decreased in nonalcoholic fatty liver patients as compared with normal subjects (10).…”

Section: Resultsmentioning

confidence: 93%

Effects of chronic ingestion of catechin-rich green tea on hepatic gene expression of gluconeogenic enzymes in rats

et al. 2009

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Normal rats were given catechin-rich green tea as drinking fluid and the effects on hepatic gene expression were examined. The results of DNA microarray analysis and quantitative real-time reverse transcription-polymerase chain reaction indicated the down-regulated expression of genes for glucose-6-phosphatase (G6Pase) and fatty acid synthase, and the up-regulated expression of peroxisome proliferator activated receptor α in the rats given green tea for 4 weeks as compared with the water-given animals. One may expect anti-diabetic activity by catechin-rich green tea through its chronic down-regulatory effect on G6Pase expression.

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Section: Resultsmentioning

confidence: 93%

Effects of chronic ingestion of catechin-rich green tea on hepatic gene expression of gluconeogenic enzymes in rats

et al. 2009

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“…Malonyl-CoA production is regulated by ACC1 and ACC2, while degradation is dependent upon the activity of malonyl-CoA decarboxylase (MCD). ACC1 234:1 expression and activity increases in fatty liver disease, while ACC2 expression is independent of hepatic lipid accumulation (Yahagi et al 2005, Kennedy et al 2007, Kohjima et al 2007). This increase in total ACC activity increases malonyl-CoA synthesis, hepatic malonyl-CoA concentration and flux through fatty acid synthesis (Zhao et al 2009).…”

Section: The Interplay Of Dnl and Beta-oxidationmentioning

confidence: 99%

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

Geisler

Renquist

2017

Journal of Endocrinology

155

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Fatty liver can be diet, endocrine, drug, virus or genetically induced. Independent of cause, hepatic lipid accumulation promotes systemic metabolic dysfunction. By acting as peroxisome proliferator-activated receptor (PPAR) ligands, hepatic non-esterified fatty acids upregulate expression of gluconeogenic, beta-oxidative, lipogenic and ketogenic genes, promoting hyperglycemia, hyperlipidemia and ketosis. The typical hormonal environment in fatty liver disease consists of hyperinsulinemia, hyperglucagonemia, hypercortisolemia, growth hormone deficiency and elevated sympathetic tone. These endocrine and metabolic changes further encourage hepatic steatosis by regulating adipose tissue lipolysis, liver lipid uptake, de novo lipogenesis (DNL), beta-oxidation, ketogenesis and lipid export. Hepatic lipid accumulation may be induced by 4 separate mechanisms: (1) increased hepatic uptake of circulating fatty acids, (2) increased hepatic de novo fatty acid synthesis, (3) decreased hepatic beta-oxidation and (4) decreased hepatic lipid export. This review will discuss the hormonal regulation of each mechanism comparing multiple physiological models of hepatic lipid accumulation. Nonalcoholic fatty liver disease (NAFLD) is typified by increased hepatic lipid uptake, synthesis, oxidation and export. Chronic hepatic lipid signaling through PPARgamma results in gene expression changes that allow concurrent activity of DNL and beta-oxidation. The importance of hepatic steatosis in driving systemic metabolic dysfunction is highlighted by the common endocrine and metabolic disturbances across many conditions that result in fatty liver. Understanding the mechanisms underlying the metabolic dysfunction that develops as a consequence of hepatic lipid accumulation is critical to identifying points of intervention in this increasingly prevalent disease state.

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“…Therefore, it is important to understand the features of lipid metabolism, particularly fatty acid metabolism, in NAFLD. Previously, we evaluated the expression levels of genes involved in fatty acid metabolism in the liver with NAFLD and found that the expression of those genes including acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), was up-regulated, indicating that fatty acid synthesis was enhanced in hepatocytes, leading to the accumulation of fatty acids (9,10).…”

Section: Introductionmentioning

confidence: 99%

SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease

Kohjima

Higuchi

Kato³

et al. 2008

Int J Mol Med

Self Cite

245

231

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Abstract. Nonalcoholic fatty liver disease (NAFLD) is a common liver disease whose prevalence has increased markedly. We reported previously that fatty acid synthesis was enhanced in NAFLD with the accumulation of fatty acids. To clarify the disorder, we evaluated the expression of genes regulating fatty acid synthesis by real-time PCR using samples from NAFLD (n=22) and normal liver (control; n=10). A major regulator of fatty acids synthesis is sterol regulatory element-binding protein-1c (SREBP-1c). Its expression was significantly higher in NAFLD, nearly 5-fold greater than the controls. SREBP-1c is positively regulated by insulin signaling pathways, including insulin receptor substrate (IRS)-1 and -2. In NAFLD, IRS-1 expression was enhanced and correlated positively with SREBP-1c expression. In contrast, IRS-2 expression decreased by 50% and was not correlated with SREBP-1c. Forkhead box protein A2 (Foxa2) is a positive regulator of fatty acid oxidation and is itself negatively regulated by IRSs. Foxa2 expression increased in NAFLD and showed a negative correlation with IRS-2, but not with IRS-1, expression. It is known that SREBP-1c is negatively regulated by AMPactivated protein kinase (AMPK) but expression levels of AMPK in NAFLD were almost equal to those of the controls. These data indicate that, in NAFLD, insulin signaling via IRS-1 causes the up-regulation of SREBP1-c, leading to the increased synthesis of fatty acids by the hepatocytes; negative feedback regulation via AMPK does not occur and the activation of Foxa2, following a decrease of IRS-2, upregulates fatty acid oxidation. IntroductionNonalcoholic fatty liver disease (NAFLD) is one of the most frequent causes of liver dysfunction (1-3) and its prevalence has been increasing markedly (4-6). Furthermore, nonalcoholic steatohepatitis (NASH), a severe form of NAFLD accompanied by hepatitis and fibrosis, may progress to cirrhosis and hepatic failure (7,8). NAFLD is often found in patients with obesity and/or insulin resistance, however, its precise cause remains unclear. Therefore, it is important to understand the features of lipid metabolism, particularly fatty acid metabolism, in NAFLD. Previously, we evaluated the expression levels of genes involved in fatty acid metabolism in the liver with NAFLD and found that the expression of those genes including acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), was up-regulated, indicating that fatty acid synthesis was enhanced in hepatocytes, leading to the accumulation of fatty acids (9,10).Sterol regulatory element-binding proteins (SREBPs) are membrane-bound transcription factors that regulate the expression of genes involved in lipid synthesis, and SREBP-1c positively regulates the expression of genes encoding lipogenic enzymes including ACC and FAS (11,12). Insulin is a well-known stimulator of lipogenesis and activates the hepatic expression of 14). Insulin receptor substrate (IRS) proteins, a family of docking molecules, connect insulin receptor activation to essential downstream cascad...

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Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease

Cited by 313 publications

References 30 publications

Effects of chronic ingestion of catechin-rich green tea on hepatic gene expression of gluconeogenic enzymes in rats

Effects of chronic ingestion of catechin-rich green tea on hepatic gene expression of gluconeogenic enzymes in rats

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease

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