Nadph

G6PD PGDH NADP+ NADP+

6-Phospho-gluconate

Saturated fatty acids

^Stearoyl-CoA desaturase NADPH, onounsaturated fatty acids

Squalene

Squalene epoxidase Lanosterol synthase CYP51

Lathosterol oxidase DHCR

Choiesteroi

LDL receptor

Fatty acyl CoA GPAT

Monoacylglycerol 3-phosphate

Triacylglycerides and phospholipids

▲ FIGURE 18-18 Global regulation of cellular lipid metabolism by SREBP! SREBP controls the transcription of genes indicated here encoding key proteins directly required for the synthesis and import of cholesterol and for the synthesis of fatty acids, phospholipids, and triglycerides. SREBPs also regulate the activity of genes in the production of NADPH, which is an energy source for many of the steps in these biosynthetic pathways. Abbreviations: GPP = geranylgeranyl pyrophosphate; IPP = isopentenyl pyrophosphate; FPP = farnesyl pyrophosphate; CYP51 = lanosterol 14a-demethylase; DHCR = 7-dehydro-cholesterol reductase; G6PD = glucose 6-phosphate dehydrogenase; PGDH = 6-phosphogluconate dehydrogenase; GPAT = glycerol 3-phosphate acyl transferase. [Adapted from J. D. Horton, J. L. Goldstein, and M. S. Brown, 2002, J. Ciin. Invest. 109:1128.]

cells sometimes need greater amounts of some lipids than others (differential regulation). For example, cells that are producing bile acids or steroid hormones need an increased supply of cholesterol but not of fatty acids or phospholipids. The complex regulation of lipid metabolism characteristic of higher eukaryotes is due largely to a plethora of transcription factors, including multiple SREBPs, that control the expression of proteins taking part in the synthesis, degradation, transport, and storage of lipids.

There are three known isoforms of SREBP in mammals: SREBP-1a and SREBP-1c, which are generated from alternatively spliced RNAs produced from the same gene, and SREBP-2, which is encoded by a different gene. Together these protease-regulated transcription factors control the availability not only of cholesterol but also of fatty acids and their products triglycerides and phospholipids. In mammalian cells, SREBP-1a and SREBP-1c exert a greater influence on fatty acid metabolism than on cholesterol metabolism, whereas the reverse is the case for SREBP-2. As indicated in Figure 18-18, SREBPs can regulate the activities of genes encoding many different proteins. Such proteins include those participating in the cellular uptake of lipids (e.g., the LDL receptor, SR-BI, and lipoprotein lipase) and numerous enzymes in the pathways for synthesizing cholesterol, fatty acids, triglycerides, and phospholipids.

0 SREBP-1 may play an important role in the development of fatty liver, a major pathologic consequence of alcohol abuse. In fatty liver, abnormally high levels of triglycerides and cholesterol accumulate in the cytosol as lipid droplets, which can contribute to alcoholic hepatitis and cirrhosis. The results of experiments using cultured hepatocytes and mice suggest that the metabolism of alcohol to acetaldehyde by hepatic alcohol dehydrogenase leads to the activation of SREBP-1 and the release of nSREBP-1, which in turn induces the synthesis of excess fatty acids and triglycerides. Consistent with this suggestion is the finding that overexpression of a truncated, constitutively active form of SREBP-1 (i.e., nSREBP-1) in the livers of mice significantly increases both fatty acid and cholesterol synthesis, resulting in a fatty liver. I

In contrast with the insig-1(2)/SCAP/SREBP pathway in mammalian cells, the homologous pathway in Drosophila does not respond to changes in cellular sterol levels. Instead, the SCAP-dependent proteolytic activation of SREBP is suppressed by high levels of phosphatidylethanolamine, the main phospholipid in fruit flies. This finding, the result of an elegant series of experiments using both enzyme inhibitors and RNA interference (RNAi), indicates that the sterol-sensing domain of Drosophila SCAP responds to the cellular level of phosphatidylethanolamine, not cholesterol. Thus so-called sterol-sensing domains might more appropriately be called lipid-sensing domains. Whether these domains directly bind to their controlling lipids or mediate interaction with other proteins that directly bind the lipids (i.e., sense the levels of the regulatory lipids) is not yet known.

As mentioned previously, HMG-CoA reductase also contains a sterol-sensing domain. This domain senses high levels of cholesterol, some cholesterol derivatives, and certain non-steroidal precursors of cholesterol, triggering the rapid, ubiquitin-dependent proteasomal degradation of the enzyme. As a consequence, HMG-CoA reductase activity drops, causing reduced cholesterol synthesis. Like SCAP, HMG-CoA reductase is located in the ER membrane and insig-1(2) binds to its sterol-sensing domain. This binding also is cholesterol dependent and is required for the cholesterol-dependent pro-teasomal degradation of HMG-CoA reductase. Thus mammalian insig-1(2) and the sterol-sensing domain of SCAP or HMG-CoA reductase apparently combine to form a cholesterol sensor. It seems likely that, in the course of evolution, the sterol-sensing domain and its associated proteins proved effective for recognizing various lipid molecules and were incorporated into a variety of regulatory systems for this purpose.

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