PCSK9 encodes proprotein convertase subtilisin͞kexin type 9a (PCSK9), a member of the proteinase K subfamily of subtilases. Missense mutations in PCSK9 cause an autosomal dominant form of hypercholesterolemia in humans, likely due to a gain-of-function mechanism because overexpression of either WT or mutant PCSK9 reduces hepatic LDL receptor protein (LDLR) in mice. Here, we show that livers of knockout mice lacking PCSK9 manifest increased LDLR protein but not mRNA. Increased LDLR protein led to increased clearance of circulating lipoproteins and decreased plasma cholesterol levels (46 mg͞dl in Pcsk9 ؊/؊ mice versus 96 mg͞dl in WT mice). Statins, a class of drugs that inhibit cholesterol synthesis, increase expression of sterol regulatory element-binding protein-2 (SREBP-2), a transcription factor that activates both the Ldlr and Pcsk9 genes. Statin administration to Pcsk9 ؊/؊ mice produced an exaggerated increase in LDLRs in liver and enhanced LDL clearance from plasma. These data demonstrate that PCSK9 regulates the amount of LDLR protein in liver and suggest that inhibitors of PCSK9 may act synergistically with statins to enhance LDLRs and reduce plasma cholesterol.low-density lipoprotein receptor ͉ lipoproteins ͉ proteinase ͉ sterol regulatory element-binding protein

SUMMARY Mutations in 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) cause congenital generalized lipodystrophy. To understand the molecular mechanisms underlying the metabolic complications associated with AGPAT2 deficiency, Agpat2 null mice were generated. Agpat2−/− mice develop severe lipodystrophy affecting both white and brown adipose tissue, severe insulin resistance, diabetes, and hepatic steatosis. The expression of lipogenic genes and rates of de novo fatty acid biosynthesis were increased ~4-fold in Agpat2−/− mouse livers. The mRNA and protein levels of monoacylglycerol acyltransferase isoform 1 were markedly increased in the livers of Agpat2−/− mice suggesting that the alternative monoacylglycerol pathway for triglyceride biosynthesis is activated in the absence of AGPAT2. Feeding a fat-free diet reduced liver triglycerides by ~50% in Agpat2−/− mice. These observations suggest that both dietary fat and hepatic triglyceride biosynthesis via a novel monoacylglycerol pathway may contribute to hepatic steatosis in Agpat2−/− mice.

Input subsidy programs have once again become a major plank of agricultural development strategies in Africa. Ten African governments spend roughly US$1 billion annually on input subsidy programs (ISPs), amounting to 28.6% of their public expenditures on agriculture. This article reviews the microlevel evidence on ISPs undertaken since the mid 2000s. We examine the characteristics of subsidy beneficiaries, crop response rates to fertilizer application and their influence on the performance of subsidy programs, the impacts of subsidy programs on national fertilizer use and the development of commercial input distribution systems, and finally the impact of ISPs on food price levels and poverty rates. The weight of the evidence indicates that the costs of the programs generally outweigh their benefits. Findings from other developing areas with a higher proportion of crop area under irrigation and with lower fertilizer prices-factors that should provide higher returns to fertilizer subsidies than in Africa-indicate that at least a partial reallocation of expenditures from fertilizer subsidies to R&D and infrastructure would provide higher returns to agricultural growth and poverty reduction. However, because ISPs enable governments to demonstrate tangible support to constituents, they are likely to remain on the African landscape for the foreseeable future. Hence, the study identifies ways in which benefits can be enhanced through changes in implementation modalities and complementary investments within a holistic agricultural intensification strategy. Among the most important of these are efforts to reduce the crowding out of commercial fertilizer distribution systems and programs to improve soil fertility to enable farmers to use fertilizer more efficiently. The challenges associated with achieving these gains are likely to be formidable. JEL classifications: O2, O13, Q12, Q18

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Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) promotes atherosclerosis by increasing low-density lipoprotein (LDL) cholesterol levels through degradation of hepatic LDL receptors (LDLR). Studies have described the systemic effects of PCSK9 on atherosclerosis, but whether PCSK9 has local and direct effects on the plaque in unknown. To study the local effect of human PCSK9 (hPCSK9) on atherosclerotic lesion composition independently of changes in serum cholesterol levels we generated chimeric mice expressing hPCSK9 exclusively from macrophages using marrow from hPCSK9 transgenic (hPCSK9tg) mice transplanted into apoE−/− and LDLR−/− mice, which were then placed on a high fat diet for 8 wk. We further characterized the effect of hPCSK9 expression on the inflammatory responses in the spleen and by mouse peritoneal macrophages (MPM) in vitro. We found that MPM from transgenic mice express both murine (m) Pcsk9 and hPCSK9 and that the latter reduces macrophage LDLR and LRP1 surface levels. hPCSK9 was detected in serum of mice transplanted with hPCSK9tg marrow, but did not influence lipid levels or atherosclerotic lesion size. However, marrow-derived PCSK9 progressively accumulated in lesions of apoE−/− recipient mice while increasing the infiltration of Ly6Chi inflammatory monocytes by 32% compared with controls. Expression of hPCSK9 also increased CD11b and Ly6Chi positive cell numbers in spleens of apoE−/− mice. In vitro, expression of hPCSK9 in LPS-stimulated macrophages increased mRNA levels of the pro-inflammatory markers Tnf and Il1b (40% and 45%, respectively) and suppressed those of the anti-inflammatory markers Il10 and Arg1 (30% and 44%, respectively). All PCSK9 effects were LDLR-dependent as PCSK9 protein was not detected in lesions of LDLR−/− recipient mice and did not affect macrophage or splenocyte inflammation. In conclusion, PCSK9 directly increases atherosclerotic lesion inflammation in an LDLR-dependent but cholesterol-independent mechanism, suggesting that therapeutic PCSK9 inhibition may have vascular benefits secondary to LDL reduction.