Loss-of-Function
            <i>CREB3L3</i>
            Variants in Patients With Severe Hypertriglyceridemia

Dron, Jacqueline S.; Dilliott, Allison A.; Lawson, Arden; McIntyre, Adam D.; Davis, Brent D.; Wang, Jian; Cao, Henian; Movsesyan, Irina; Malloy, Mary J.; Pullinger, Clive R.; Kane, John P.; Hegele, Robert A.

doi:10.1161/atvbaha.120.314168

Cited by 21 publications

(17 citation statements)

References 45 publications

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“…Importantly, humans with heterozygous CREB3L3 loss-of-function or missense mutations exhibit hypertriglyceridemia (3,4). Furthermore, a recent study found that individuals with severe hypertriglyceridemia were 20 times more likely than controls to carry loss-of-function mutations in CREB3L3 (5). Because CREB3L3 loss-of-function mutations are rare, it is not yet known if such individuals exhibit an increased cardiovascular disease risk.…”

Section: Introductionmentioning

confidence: 99%

CREBH normalizes dyslipidemia and halts atherosclerosis in diabetes by decreasing circulating remnant lipoproteins

Shimizu‐Albergine¹,

Basu²,

Kanter³

et al. 2021

Journal of Clinical Investigation

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Loss-of-function mutations in the transcription factor CREB3L3 (CREBH) associate with severe hypertriglyceridemia in humans. CREBH is believed to lower plasma triglycerides by augmenting the action of lipoprotein lipase (LPL). However, by using a mouse model of type 1 diabetes mellitus (T1DM), we found that greater liver expression of active CREBH normalized both elevated plasma triglycerides and cholesterol.Residual triglyceride-rich lipoprotein (TRL) remnants were enriched in apolipoprotein E (APOE) and impoverished in APOC3, an apolipoprotein composition indicative of increased hepatic clearance. The underlying mechanism was independent of LPL as CREBH reduced both triglycerides and cholesterol in LPL-deficient mice. Instead, APOE was critical for CREBH's ability to lower circulating remnant lipoproteins because it failed to reduce TRL cholesterol in Apoe -/mice. Importantly, humans with CREB3L3 loss-of-function mutations exhibited increased levels of remnant lipoproteins that were deprived of APOE. Recent evidence suggests that impaired clearance of TRL remnants promotes cardiovascular disease in patients with T1DM. Consistently, we found that hepatic expression of CREBH prevented the progression of diabetes-accelerated atherosclerosis. Our results support the proposal that CREBH acts through an APOEdependent pathway to increase hepatic clearance of remnant lipoproteins. They also implicate elevated levels of remnants in the pathogenesis of atherosclerosis in T1DM.

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Section: Introductionmentioning

confidence: 99%

CREBH normalizes dyslipidemia and halts atherosclerosis in diabetes by decreasing circulating remnant lipoproteins

Shimizu‐Albergine¹,

Basu²,

Kanter³

et al. 2021

Journal of Clinical Investigation

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“…This group of disorders are the most frequent cause of the CS, occurring in about 1;600 of the population (3,7,9,10). They are thought to result from the clustering of multiple genetic variants that include both rare heterozygous variants of the LPL, APOC2, APOA5, APOB, GCKR, LMF1, and GPIHBP1 genes and more frequent variants with small effects in~40 genes.…”

Section: Polygenic Causes Of Hypertriglyceridemia-multifactorial Chylmentioning

confidence: 99%

“…They are thought to result from the clustering of multiple genetic variants that include both rare heterozygous variants of the LPL, APOC2, APOA5, APOB, GCKR, LMF1, and GPIHBP1 genes and more frequent variants with small effects in~40 genes. Recently, CREB3L3, the gene for the transcription factor cyclic AMP-responsive element-binding protein H (CREBH), which is induced by metabolic cues such as fasting and fatty acids and leads to increases in APOC2 and APOA5 and reduction in APOC3 production has been shown to be associated with MFCS (10). In most cases these genetic variants are thought to require an aggravating effect of one or more secondary conditions or medications that exacerbate the metabolic defect leading to saturation of clearance mechanisms to cause the CS.…”

Section: Polygenic Causes Of Hypertriglyceridemia-multifactorial Chylmentioning

confidence: 99%

“…In most cases these genetic variants are thought to require an aggravating effect of one or more secondary conditions or medications that exacerbate the metabolic defect leading to saturation of clearance mechanisms to cause the CS. In a recent survey of the genetic determinants of severe HTG in 567 subjects, 1.1% had homozygous or compound heterozygous rare variants (FCS), 14.4% had heterozygous rare variants among which heterozygous mutations of the LPL, APOA5 and CREB3L3 genes were most frequent, 32.0% had an extreme accumulation of common variants and 52.6% remained genetically undefined (10). Common genetic variants influence triglyceride levels in the general population and the presence of multiple common variants, each with small effects in an individual, and constituting a polygenic risk score, interacts with secondary factors to cause mild to moderate HTG, the clinical phenotype of polygenic HTG (11).…”

Section: Polygenic Causes Of Hypertriglyceridemia-multifactorial Chylmentioning

confidence: 99%

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A Comprehensive Update on the Chylomicronemia Syndrome

Goldberg

Chait

2020

Front. Endocrinol.

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The chylomicronemia syndrome is characterized by severe hypertriglyceridemia and fasting chylomicronemia and predisposes affected individuals to acute pancreatitis. When due to very rare monogenic mutations in the genes encoding the enzyme, lipoprotein lipase, or its regulators, APOC2, APOA5, GPIHBP1, and LMF1, it is referred to as the familial chylomicronemia syndrome. Much more frequently, the chylomicronemia syndrome results from a cluster of minor genetic variants causing polygenic hypertriglyceridemia, which is exacerbated by conditions or medications which increase triglyceride levels beyond the saturation point of triglyceride removal systems. This situation is termed the multifactorial chylomicronemia syndrome. These aggravating factors include common conditions such as uncontrolled diabetes, overweight and obesity, alcohol excess, chronic kidney disease and pregnancy and several medications, including diuretics, non-selective beta blockers, estrogenic compounds, corticosteroids, protease inhibitors, immunosuppressives, antipsychotics, antidepressants, retinoids, L-asparaginase, and propofol. A third uncommon cause of the chylomicronemia syndrome is familial forms of partial lipodystrophy. Development of pancreatitis is the most feared complication of the chylomicronemia syndrome, but the risk of cardiovascular disease as well as non-alcoholic steatohepatitis is also increased. Treatment consists of dietary fat restriction and weight reduction combined with the use of triglyceride lowering medications such as fibrates, omega 3 fatty acids and niacin. Effective management of aggravating factors such as improving diabetes control, discontinuing alcohol and replacing or reducing the dose of medications that raise triglyceride levels is essential. Importantly, many if not most cases of the chylomicronemia syndrome can be prevented by effective identification of polygenic hypertriglyceridemia in people with conditions that increase its likelihood or before starting medications that may increase triglyceride levels. Several new pharmacotherapeutic agents are being tested that are likely to considerably improve treatment of hypertriglyceridemia in people at risk.

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“…Because there is a difference in lipid metabolism between rodents and human beings, the pathophysiological relevance of these findings needs to be confirmed in future clinical studies. Second, multiple nonsynonymous mutations in CREB3L3 that produce a hypomorphic or nonfunctional Creb3L3 protein were identified in patients with extreme hypertriglyceridemia 14,19 ; it remains to be analyzed how these mutations affect the antagonism of CREB3L3 by SREBP. Other important aspects that also remain to be characterized are the binding domains for the interaction of SREBP and CREB3L3, as well as other novel interacting partners of the CREB3L3-SREBP complex.…”

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confidence: 99%

Making the Best of a Competition: the CREB3L3–SREBP Axis in Arteriosclerosis

Pradhan‐Sundd

2021

Cellular and Molecular Gastroenterology and Hepatology

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Making the Best of a Competition: the CREB3L3-SREBP Axis in Arteriosclerosis O besity is a serious global health burden, with more than 2 billion people being overweight, of whom approximately one-third suffer from obesity. 1,2 Abdominal obesity is linked to various cardiovascular and metabolic disorders, including arteriosclerosis, which is a leading cause of mortality and morbidity worldwide. 3 Arteriosclerosis is controlled directly by lipid metabolism, which is orchestrated by a network of transcription factors. 4-6 The cyclic AMP-responsive element-binding protein 3 like 3 (CREB3L3) is a membrane-bound transcription factor that is expressed exclusively in the liver and intestine and controls multiple metabolic functions, including glucose and lipid metabolism and cholesterol absorption. 7-9 The metabolic consequences of CREB3L3 gene ablation or overexpression have been studied extensively in the past decade. 5,9-11 Whereas CREB3L3 deficiency leads to massive accumulation of hepatic lipids and to an increase in plasma triglyceride (TG) levels, its overexpression reduces plasma TG levels by promoting the hepatic expression of regulators of arteriosclerosis, such as apolipoprotein A4 (Apoa4), Apoa5, and Apoc2. 10,12-14 Loss of CREB3L3 in a common mouse model of arteriosclerosis (low density lipoprotein receptor [LDLR-/-] mice) increases the frequency of arteriosclerotic lesions, indicating a critical contribution of CREB3L3 to arteriosclerosis. 13 Although much has been learned about the physiological functions of CREB3L3, the action of CREB3L3 at the hepatic and intestinal levels is still an emerging area of research, as is that on CREB3L3interacting partners. The study by Nakagawa et al 15 in this issue of Cellular and Molecular Gastroenterology Hepatology sheds additional light on the emerging role of CREB3L3 in arteriosclerosis. Using elegant murine models with liver-and intestinespecific CREB3L3 null mutations, Nakagawa et al 15 remarkably showed that both liver-and intestine-specific CREB3L3 deficiency additively promoted arteriosclerosis. Moreover, the overexpression of CREB3L3 suppressed the formation of arteriosclerotic lesions in LDLR-/mice. They showed that CREB3L3 regulates arteriosclerosis by promoting the activation of antiatherogenic fibroblast growth factor (FGF)21 and APOA4, and inhibiting sterol regulatory element-binding proteins (SREBPs), key transcriptional regulators of cholesterol and lipid metabolism. 16 Although the control of FGF21 and APOA4 expression by CREB3L3 was expected, 5,12,14 the characterization of the molecular competition between SREBP and CREB3L3 is novel to the current work. Mechanistically, Nakagawa et al 15 found that the antagonism between CREB3L3 and SREBP occurs during trafficking from the endoplasmic reticulum (ER) to the

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Loss-of-Function CREB3L3 Variants in Patients With Severe Hypertriglyceridemia

Cited by 21 publications

References 45 publications

CREBH normalizes dyslipidemia and halts atherosclerosis in diabetes by decreasing circulating remnant lipoproteins

CREBH normalizes dyslipidemia and halts atherosclerosis in diabetes by decreasing circulating remnant lipoproteins

A Comprehensive Update on the Chylomicronemia Syndrome

Making the Best of a Competition: the CREB3L3–SREBP Axis in Arteriosclerosis

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