Polyunsaturated Fatty Acids Selectively Suppress Sterol Regulatory Element-binding Protein-1 through Proteolytic Processing and Autoloop Regulatory Circuit

Abstract

Sterol regulatory element-binding protein (SREBP)-1 is a key transcription factor for the regulation of lipogenic enzyme genes in the liver. Polyunsaturated fatty acids (PUFA) selectively suppress hepatic SREBP-1, but molecular mechanisms remain largely unknown. To gain insight into this regulation, we established in vivo reporter assays to assess the activities of Srebf1c transcription and proteolytic processing. Using these in vivo reporter assays, we showed that the primary mechanism for PUFA suppression of SREBP-1 is at the proteolytic processing level and that this suppression in turn decreases the mRNA transcription through lowering SREBP-1 binding to the SREBPbinding element on the promoter ("autoloop regulatory circuit"), although liver X receptor, an activator for Srebf1c transcription, is not involved in this regulation by PUFA. The mechanisms for PUFA suppression of SREBP-1 confirm that the autoloop regulation for transcription is crucial for the nutritional regulation of triglyceride synthesis. Polyunsaturated fatty acids (PUFA)3 have been well established as negative regulators of hepatic lipogenesis (reviewed in Ref. 1). Allmann and Gibson (2) discovered that adding 2% linoleate to a high carbohydrate fat-free diet suppressed the rate of hepatic fatty acid biosynthesis and the activities of fatty-acid synthase 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, a number of 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 acetyl-CoA carboxylase, fatty-acid synthase, and stearoyl-CoA desaturase.The fatty acid biosynthetic pathway, composed of some 25 enzymes, has been elucidated in detail (3). For the de novo synthesis of long chain saturated fatty acids, fatty-acid synthase, the main synthetic enzyme that catalyzes the condensation of malonyl-CoA to produce the 16-carbon saturated fatty acid palmitate, and acetyl-CoA carboxylase, which synthesizes malonyl-CoA from acetyl-CoA, are of particular importance. The regulation of these lipogenic enzymes has been revealed to be primarily controlled by a transcription factor sterol regulatory element-binding protein (SREBP)-1c (4, 5).SREBPs are transcription factors that belong to the basic helix-loop-helix leucine zipper family and are considered to be profoundly involved in the transcriptional regulation of cholesterogenic and lipogenic enzymes (6, 7). 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 cleaved, and the N-terminal parts are released from the membrane into the nucleus as mature protein by a sequential two-step proteolytic processing. To date, three SREBP isof...

Effects of short- and long-chain fatty acids on the expression of stearoyl-CoA desaturase and other lipogenic genes in bovine mammary epithelial cells

“…A similar relationship between SREBF1 and INSIG1 mRNA expression was observed in vivo in the bovine mammary gland after dietary intake of C18:2 trans-10, cis-12 CLA (Harvatine and Bauman, 2006), providing strong support for SREBF1 as a central signalling pathway regulating FA synthesis in the bovine mammary gland (Ma and Corl, 2012). Our findings are also most consistent with a model in which PUFA suppress the expression of lipogenic genes by decreasing the nuclear content of transcription factor SREBF1 through inhibition of the proteolytic processing of SREBF1 in the Golgi apparatus (Xu et al, 2001;Takeuchi et al, 2010). Alternatively, PUFA may also modulate the interaction of lipogenic transcription factors with the promoter of lipogenic genes directly, as reported for the hepatic FASN gene (Teran-Garcia et al, 2007).…”

Impact of dietary fat quantity and quality on skeletal muscle fatty acid metabolism in subjects with the metabolic syndrome

“…These data indicate a shift towards a lower accumulation of lipids in muscle on the diets high in MUFA or high in complex carbohydrates with n-3 supplement, which is dependent on the initial degree of insulin sensitivity (or insulin resistance). The primary mechanism for PUFA or MUFA to regulate SREBP1c mRNA may be related to the suppression of proteolytic processing, which in turn reduces mRNA transcription [33]. Low SREBP1c and ACC2 mRNA levels may lead to reduced malonyl-CoA concentration (via a reduction in ACC2 mRNA expression), and subsequently FAs are directed towards oxidation instead of storage [34].…”

The Effect of Diet on the Response of Low-density Lipoprotein Receptor Knockout Mice to the Liver X Receptor Agonist T1317

“…Polyunsaturated fatty acids can decrease the expression of SREBP-1c by inhibiting the processing of the membrane bound SREBP-1c precursor to a mature nuclear form that is capable of activating gene transcription, including its own gene. 19 Polyunsaturated fatty acids modulate SREBP-1c function when given at doses of 2.5-10 gÁkg 21 Ád 21 . 19 The Paigen and Western diets with 2%-4% PUFAs provide a dose of about 0.1-0.2 g of PUFA per day for a mouse eating 5 g of food per day that would provide for a dosage of 5-10 g of PUFA per kilogram per day, more than sufficient to affect SREBP-1c processing.…”

“…19 Polyunsaturated fatty acids modulate SREBP-1c function when given at doses of 2.5-10 gÁkg 21 Ád 21 . 19 The Paigen and Western diets with 2%-4% PUFAs provide a dose of about 0.1-0.2 g of PUFA per day for a mouse eating 5 g of food per day that would provide for a dosage of 5-10 g of PUFA per kilogram per day, more than sufficient to affect SREBP-1c processing. However, both diets contain similar levels of PUFAs, and so they are unlikely responsible for the transient versus persistent difference in serum triglycerides.…”