A Crucial Role of Sterol Regulatory Element-binding Protein-1 in the Regulation of Lipogenic Gene Expression by Polyunsaturated Fatty Acids

Abstract

The liver, the principal lipogenic organ, is responsible for the conversion of excess dietary carbohydrates to triglycerides. A high carbohydrate diet induces the synthesis of several lipogenic and glycolytic enzymes including acetyl-CoA carboxylase (ACC), 1 fatty acid synthase (FAS), stearoyl-CoA desaturase, ATP citrate lyase, malic enzyme, glucose-6-phosphate dehydrogenase, and pyruvate kinase (PK) (1-3). This coordinate induction of enzymes is due to increased mRNA levels, resulting primarily from the accelerated transcription.Dietary polyunsaturated fatty acids (PUFA) have been well established as negative regulators of hepatic lipogenesis. Allmann and Gibson (4) discovered that adding 2% linoleate to a high carbohydrate fat-free diet suppressed the rate of hepatic fatty acid biosynthesis and the activities of FAS and glucose-6-phosphate dehydrogenase by nearly 70% in mice. In contrast, supplementing the high carbohydrate diet with palmitate, oleate, or cholesterol had no effect on hepatic lipogenesis or the activity of lipogenic enzymes. Since then, several investigators have demonstrated that dietary PUFA of the n-6 and n-3 families suppress hepatic lipogenesis. This anti-lipogenic action of PUFA reflects decreases in mRNA levels of hepatic enzymes including ACC, FAS, stearoyl-CoA desaturase, ATP citrate lyase, malic enzyme, glucose-6-phosphate dehydrogenase, and PK. The regulation by PUFA has been shown to be primarily at the transcriptional level; however, the precise mechanism for this action remains unknown (5-7).Sterol regulatory element-binding proteins (SREBPs) are transcription factors that belong to the basic helix-loop-helixleucine zipper family and regulate enzymes responsible for the synthesis of cholesterol, fatty acids, and triglycerides (8). Unlike other members of the basic helix-loop-helix-leucine zipper family, SREBPs are synthesized as precursors bound to the endoplasmic reticulum and nuclear envelope. Upon activation, SREBPs are released from the membrane into the nucleus as a mature protein by a sequential two-step cleavage process. To date, three SREBP isoforms, SREBP-1a, -1c and -2, have been identified and characterized. The predominant SREBP-1 isoform in the liver is SREBP-1c. Whereas SREBP-2 is relatively selective in transcriptionally activating cholesterol biosynthetic genes, SREBP-1c has a greater role in regulating fatty acid synthesis than cholesterol synthesis in the liver (9 -11, 30).The role of SREBP-1 for the regulation of hepatic lipogenesis has been recently established. Changes in hepatic mature SREBP-1c protein levels were shown to parallel those of mRNAs for lipogenic genes in the liver using a dietary manipulation and a transgenic technology (12). Moreover, SREBP-1 has been demonstrated to be crucial for the carbohydrate stimulation of lipogenic genes in mice with a targeted disruption of SREBP-1 (30).

Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression

“…To investigate whether the reduction of triglyceride in liver can be ascribed to the decrease in mature SREBP-1, we examined a transgenic mouse model, which forcibly expresses a mature form of SREBP-1 protein in the liver (TgSREBP1). Consistent with a previous report, 10 dietary PUFA did not decrease the mature SREBP-1 protein or the mRNA levels of lipogenic genes in the liver of TgSREBP1 mice (data not shown). Accordingly, the triglyceride content of EPA-fed mice was almost equal to mice fed the control diet (Fig.…”

“…Based on our previous findings that PUFAs suppress SREBP-1 10 and that SREBP-1-null ob/ob mice have less triglycerides in liver, 5 we hypothesized that PUFA would decrease hepatic triglyceride storage through the reduction of SREBP-1. Our results provide a strong clinical implication that PUFAs are potentially useful for the treatment of hepatic steatosis.…”

Dietary fat modifies lipid metabolism in the adipose tissue of metabolic syndrome patients

“…This idea is supported by the fact that the overexpression of mature SREBP1 overrides the PUFA suppression of lipogenic gene expression (Yahagi et al 1999), and by a study using animal models which showed that the decrease of the mature form of SREBP1 after administration of fish oil rich in n-3 PUFA results in decreased expression of lipogenic enzymes including SCD1 (Xu et al 1999). Moreover, n-3 PUFA has been related to the control of the proteolytic processing of SREBP precursors (Pegorier et al 2004) and its modulator effect in decreasing the lipogenesis process through inhibition of SREBP1 in adipocytes (Madsen et al 2005).…”

The effects of dietary α-linolenic acid on growth performance, meat quality, fatty acid composition and liver relative enzyme mRNA expression of growing meat rabbits

“…Bing et al (1996) pointed out that lipo genic gene transcription is inhibited by polyunsatu rated fatty acids and illustrated that the suppression of hepatic lipogenesis is due, at least in part, to the inhibition of transcription of several genes encod ing proteins involved in both lipogenesis and gly colysis, including fatty acid synthase, stearoyl-CoA desaturase, L-type pyruvate kinase, and the S14 protein. Yahagi et al (1999) also demonstrated that ACC expression in mice may be downregulated by dietary PUFAs. At the same time, ACC mRNA ex pression in the liver of meat rabbits was depressed by dietary ALA. Chatelain et al (1996) reported that the rapid increase in the hepatic CPT 1 mRNA level that ac companies the foetal to neonatal transition in the rat is triggered by the reciprocal change in circu lating insulin and long-chain fatty acid concentra tions.…”