Mitochondrial dysfunction precedes insulin resistance and hepatic steatosis and contributes to the natural history of non-alcoholic fatty liver disease in an obese rodent model

Shin

Laboratory Investigation

et al. 2014

219

172

Non-alcoholic fatty liver disease (NAFLD) is currently one of the most common types of chronic liver injury. Elevated serum uric acid is a strong predictor of the development of fatty liver as well as metabolic syndrome. Here we demonstrate that uric acid induces triglyceride accumulation by SREBP-1c activation via induction of endoplasmic reticulum (ER) stress in hepatocytes. Uric acid-induced ER stress resulted in an increase of glucose-regulated protein (GRP78/94), splicing of the X-box-binding protein-1 (XBP-1), the phosphorylation of protein kinase RNA-like ER kinase (PERK), and eukaryotic translation initiation factor-2a (eIF-2a) in cultured hepatocytes. Uric acid promoted hepatic lipogenesis through overexpression of the lipogenic enzyme, acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD1) via activation of SREBP-1c, which was blocked by probenecid, an organic anion transport blocker in HepG2 cells and primary hepatocytes. A blocker of ER stress, tauroursodeoxycholic acid (TUDCA), and an inhibitor of SREBP-1c, metformin, blocked hepatic fat accumulation, suggesting that uric acid promoted fat synthesis in hepatocytes via ER stress-induced activation of SREBP-1c. Uric acid-induced activation of NADPH oxidase preceded ER stress, which further induced mitochondrial ROS production in hepatocytes. These studies provide new insights into the mechanisms by which uric acid stimulates fat accumulation in the liver.

Section: Discussionsupporting

confidence: 56%

Uric acid induces fat accumulation via generation of endoplasmic reticulum stress and SREBP-1c activation in hepatocytes

Shin

Laboratory Investigation

et al. 2014

219

172

Laboratory Investigation

“…37,38 By contrast, a reduction of CPT-1 activity along with other mitochondrial defects, which preceded the development of steatosis and NASH, has been implicated as leading cause for disease development in the Otsuka Long-Evans Tokushima Fatty rat model of NASH. 39 In further support of a contribution of impaired mitochondrial b-oxidation to steatosis, inhibition of CPT-1 has been identified as a possible underlying mechanism in drug-induced steatosis. 40 Development of steatosis was also favored by other defects of mitochondrial b-oxidation such as heterozygous deletion of mitochondrial trifunctional protein or knockdown of long chain acyl-CoA dehydrogenase.…”

Section: Discussionmentioning

confidence: 97%

Stimulation of fat accumulation in hepatocytes by PGE2-dependent repression of hepatic lipolysis, β-oxidation and VLDL-synthesis

Henkel

Frede

Schanze

et al. 2012

Hepatic steatosis is recognized as hepatic presentation of the metabolic syndrome. Hyperinsulinaemia, which shifts fatty acid oxidation to de novo lipogenesis and lipid storage in the liver, appears to be a principal elicitor particularly in the early stages of disease development. The impact of PGE 2 , which has previously been shown to attenuate insulin signaling and hence might reduce insulin-dependent lipid accumulation, on insulin-induced steatosis of hepatocytes was studied. The PGE 2 -generating capacity was enhanced in various obese mouse models by the induction of cyclooxygenase 2 and microsomal prostaglandin E-synthases (mPGES1, mPGES2). PGE 2 attenuated the insulin-dependent induction of SREBP-1c and its target genes glucokinase and fatty acid synthase. Nevertheless, PGE 2 enhanced incorporation of glucose into hepatic triglycerides synergistically with insulin. This was most likely due to a combination of a PGE 2 -dependent repression of (1) the key lipolytic enzyme adipose triglyceride lipase, (2) carnitine-palmitoyltransferase 1, a key regulator of mitochondrial b-oxidation, and (3) microsomal transfer protein, as well as (4) apolipoprotein B, key components of the VLDL synthesis. Repression of PGC1a, a common upstream regulator of these genes, was identified as a possible cause. In support of this hypothesis, overexpression of PGC1a completely blunted the PGE 2 -dependent fat accumulation. PGE 2 enhanced lipid accumulation synergistically with insulin, despite attenuating insulin signaling and might thus contribute to the development of hepatic steatosis. Induction of enzymes involved in PGE 2 synthesis in in vivo models of obesity imply a potential role of prostanoids in the development of NAFLD and NASH.

Digestive and Liver Disease

“…Restoring mitochondrial GSH to normal levels by the administration of GSH precursors prevents the establishment of inflammation in the MCD diet model [36]. A marked decrease of MRC activity have been evidenced in patients with NAFLD [37], and liver mitochondrial dysfunction seems to be an early pathogenetic step that precedes fatty liver in rats [38]. Mitochondria are a target of oxidative stress, but also the main source of free radicals and the impairment in MRC activity is directly responsible for the increase in cellular ROS in a vicious cycle [13].…”

Section: Discussionmentioning

confidence: 99%

Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis

Salamone¹,

Galvano²,

Marino³

et al. 2012

a b s t r a c tBackground: Nonalcoholic fatty liver disease is a chronic metabolic disorder with significant impact on cardiovascular and liver mortality. Aims: In this study, we examined the effects of silibinin on liver and myocardium injury in an experimental model of nonalcoholic fatty liver disease. Methods: A four-week daily dose of silibinin (20 mg/kg i.p.) was administrated to db/db mice fed a methionine-choline deficient diet. Hepatic and myocardial histology, oxidative stress and inflammatory cytokines were evaluated. Results: Silibinin administration decreased HOMA-IR, serum ALT and markedly improved hepatic and myocardial damage. Silibinin reduced isoprostanes, 8-deoxyguanosine and nitrites/nitrates in the liver and in the heart of db/db fed the methionine-choline deficient diet, whereas glutathione levels were restored to lean mice levels in both tissues. Consistently, liver mitochondrial respiratory chain activity was significantly impaired in untreated mice and was completely restored in silibinin-treated animals. TNF-␣ was increased whereas IL-6 was decreased both in the liver and heart of db/db fed methionine-choline deficient diet. Silibinin reversed heart TNF-␣ and IL-6 expression to control mice levels. Indeed, liver JNK phosphorylation was reduced to control levels in treated animals. Conclusions: This study demonstrates a combined effectiveness of silibinin on improving liver and myocardial injury in experimental nonalcoholic fatty liver disease.