Aberrant Hepatic Expression of PPARγ2 Stimulates Hepatic Lipogenesis in a Mouse Model of Obesity, Insulin Resistance, Dyslipidemia, and Hepatic Steatosis

Abstract

Insulin-resistant apoB/BATless mice have hypertriglyceridemia because of increased assembly and secretion of very low density apolipoprotein B (apoB) and triglycerides compared with mice expressing only apoB (Siri, P., Candela, N., Ko, C., Zhang, Y., Eusufzai, S., Ginsberg, H. N., and Huang, L. S. (2001) J. Biol. Chem. 276, 46064 -46072). Despite increased very low density lipoprotein secretion, apoB/BATless mice have fatty livers. We found that hepatic mRNA levels of key lipogenic enzymes, acetyl-CoA carboxylase, fatty-acid synthase, and stearoyl-CoA desaturase-1 were increased in apoB/BATless mice compared with levels in apoB mice, suggesting increased lipogenesis in apoB/BATless mice. This was confirmed by determining incorporation of tritiated water into fatty acids. Neither the hepatic mRNA of the lipogenic transcription factor, SREBP-1c (sterol-response element-binding protein 1c), nor the nuclear levels of the mature form of SREBP-1 protein were elevated in apoB/BATless mice. By contrast, hepatic levels of peroxisomal proliferator-activated receptor 2 (PPAR␥2) mRNA and protein were specifically increased in apoB/BATless mice, as were hepatic mRNA levels of two targets of PPAR␥, CD36 and aP2. Treatment of apoB/BATless mice for 4 weeks with intraperitoneal injections of a PPAR␥ antisense oligonucleotide resulted in dramatic reductions of both PPAR␥1 and PPAR␥2 mRNA, PPAR␥2 protein, and mRNA levels of fatty-acid synthase and acetyl-CoA carboxylase. These changes were associated with decreased hepatic de novo lipogenesis and hepatic triglyceride concentrations. We conclude that hepatic steatosis in apoB/ BATless mice is associated with elevated rates of hepatic lipogenesis that are linked directly to increased hepatic expression of PPAR␥2. The mechanism whereby hepatic Ppar␥2 gene expression is increased and how PPAR␥2 stimulates lipogenesis is under investigation.We reported previously that apoB/BATless mice, a model generated by crossing mice expressing human apolipoprotein B (apoB) 3 (1) with mice lacking brown adipose tissue (BATless) (2), have hypertriglyceridemia and hypercholesterolemia because of a 2-3-fold increase in the secretion of very low density lipoprotein (VLDL) apoB and triglycerides (TG) relative to mice expressing apoB only (3). Similar levels of apoB mRNA in the livers of apoB and apoB/BATless mice indicated that the differences in apoB secretion resulted from differences in posttranscriptional regulation of VLDL assembly and secretion (4). There were no differences in hepatic levels of microsomal triglyceride transfer protein mRNA (3), a critical factor in the early co-and post-translational regulation of apoB-containing lipoprotein secretion (5). Low density lipoprotein receptor mRNA levels in liver were higher in apoB/BATless compared with apoB mice (3), indicating that increased apoB secretion in apoB/BATless mice did not result from reduced interactions of the low density lipoprotein receptor with nascent apoB lipoproteins (6).Associated with a rising prevalence of obesity and insuli...

ATF4 Protein Deficiency Protects against High Fructose-induced Hypertriglyceridemia in Mice

“…In support of this mechanism, we showed that ATF4 depletion curbs hepatic expression of Ppar-␥, a nuclear receptor that functions in complex with retinoid X receptor to promote lipogenesis in the liver (42, 46 -48). Hepatic Ppar-␥ expression is up-regulated in mice with hepatic steatosis (44,49) or dietary obesity (50 -52). This observation is recapitulated in humans, as obese patients with hepatosteatosis exhibited markedly increased PPAR-␥ activity in the liver (53,54).…”

“…3I). Furthermore, we quantified hepatic expression levels of Ppar-␥, a nuclear receptor whose activation is linked to enhanced lipid synthesis and increased fat storage in the liver (42)(43)(44). We detected a significant reduction in hepatic Ppar-␥ expression (Fig.…”

Nuclear receptor PPARγ-regulated monoacylglycerol O -acyltransferase 1 (MGAT1) expression is responsible for the lipid accumulation in diet-induced hepatic steatosis

“…ApoB/BATless mice do not show increased levels of hepatic SREBP1c, despite the presence of insulin resistance and hyperinsulinemia (21). SREBP1c gene deletion in mice results in a 50% decrease in fatty acid synthesis, indicating that SREBP1c activity alone is not sufficient to completely eliminate fatty acid synthesis (22).…”

Suppression of Long Chain Acyl-CoA Synthetase 3 Decreases Hepatic de Novo Fatty Acid Synthesis through Decreased Transcriptional Activity

“…ACSL3 siRNAs Decrease the Transcriptional Activity of ChREBP, SREBP1-c, and LXR-␣-Although most characterization of PPAR-␥ has been reported in adipocytes (2,23), this transcription factor has also been linked to lipogenesis and lipid accumulation in liver (3,24,25). Thus, based on our initial findings that PPAR-␥ was suppressed by ACSL3 knockdown, we wanted to further characterize how ACSL3 influenced other transcription factors such as SREBP-1c, LXR-␣, and ChREBP, all of which contribute to the regulation of lipogenic gene expression.…”