Guidance for the diagnosis and treatment of hypolipidemia disorders.

The Abetalipoproteinemia and Related Disorders Foundation was established in 2019 to provide guidance and support for the life-long management of inherited hypocholesterolemia disorders. Our mission is "to improve the lives of individuals and families affected by abetalipoproteinemia and related disorders". This review explains the molecular mechanisms behind the monogenic hypobetalipoproteinemia disorders and details their specific pathophysiology, clinical presentation and management throughout the lifespan. In this review, we focus on abetalipoproteinemia, homozygous hypobetalipoproteinemia and chylomicron retention disease; rare genetic conditions that manifest early in life and cause severe complications without appropriate treatment. Absent to low plasma lipid levels, in particular cholesterol and triglyceride, along with malabsorption of fat and fat-soluble vitamins are characteristic features of these diseases. We summarize the genetic basis of these disorders, provide guidance in their diagnosis and suggest treatment regimens including high dose fat-soluble vitamins as therapeutics. A section on preconception counseling and other special considerations pertaining to pregnancy is included. This information may be useful for patients, caregivers, physicians and insurance agencies involved in the management and support of affected individuals.

Differential Effect of Four-Week Feeding of Different Dietary Fats on the Accumulation of Fat and the Cholesterol and Triglyceride Contents in the Different Fat Depots.

The aim of the present study was to determine the effects of feeding of a high-fat diet containing different types of lipids for four weeks on the cholesterol and triglyceride contents of different fat depots and on body temperature in rats. Four groups of adult rats were fed 10% fat, containing either beef tallow, safflower oil, or fish oil, respectively, as well as a normal rodent diet with 4% fat, for four weeks. The rats on normal rodent diet consumed significantly more food and water than the rats in the other three groups. Rectal temperature increased only after four-week feeding with safflower oil fat. Increased fat deposition and adipocyte size were observed in rats fed safflower oil and beef tallow. In all fat pads of safflower oil-fed rats, cholesterol content was significantly higher than the other three groups. Feeding of beef tallow increased triglyceride depot without increasing cholesterol content. The rats fed fish oil had significantly less triglyceride and cholesterol deposition in adipose tissues than the rats fed safflower oil or beef tallow. These results clearly demonstrated the differences in fat deposition, adipocyte size and number, triglyceride and cholesterol accumulation in fat cells are dependent on the dietary lipid composition.

Role of PPARα in the attenuation of bile acid-induced apoptosis by omega-3 long-chain polyunsaturated fatty acids in cultured hepatocytes.

BACKGROUND: Omega-3 long-chain polyunsaturated fatty acids (ω3PUFA) have been shown to be antiinflammatory in the attenuation of hepatocellular injury. Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor transcription factor that inhibits the activation of nuclear factor κB, thereby repressing inflammation, and ωPUFA are PPARα ligands. The purpose of this study was to determine if ω3PUFA attenuate bile acid-induced apoptosis via PPARα. METHODS: Human hepatocellular carcinoma (HepG2) cells were treated with chenodeoxycholic acid (CDCA) ± ω3PUFA. Activation of PPARα was evaluated, and expression of PPARα, farnesoid X receptor, liver X receptor alpha (LXRα), and retinoid X receptor mRNA was evaluated by reverse-transcriptase PCR. RESULTS: PPARα activation was increased in HepG2 cells treated with ω3PUFA, and decreased in the presence of CDCA when compared with untreated cells. PPARα mRNA was reduced by 67% with CDCA and restored to the level of control with ω3PUFA. LXRα mRNA increased twofold with CDCA treatment and was significantly reduced by ω3PUFA. CONCLUSION: Expression of PPARα, as well as LXRα mRNA levels, was reduced with CDCA treatment and restored with the addition of ω3PUFA. These results suggest that PPARα and LXRα may be mediators by which ω3PUFA attenuate bile acid-induced hepatocellular injury.

Eicosapentaenoic acid and docosahexaenoic acid synergistically attenuate bile acid-induced hepatocellular apoptosis.

BACKGROUND: Clinical studies have demonstrated improvement of parenteral nutrition (PN)-associated liver disease (PNALD) with ω3 polyunsaturated fatty acid (ω3PUFA) supplementation containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Experiments were designed to test the following hypotheses: (1) therapeutic effects of ω3PUFA are due to attenuation of cellular apoptosis induced by hydrophobic bile acid exposure, which occurs in cholestasis, and (2) attenuation of apoptosis by EPA and DHA is additive or synergistic. METHODS: Cultured HepG2 cells were treated with 50-200 µM chenodeoxycholic acid (CDCA) in the presence and absence of EPA, DHA, or EPA + DHA. Apoptosis was evaluated using cell staining with fluorescence microscopy and the Apo-ONE Homogeneous Caspase-3/7 assay. Specific apoptotic mediators were evaluated with quantitative RT-PCR. RESULTS: Treatment with EPA alone and DHA alone resulted in 22% and 9% attenuation of caspase-3/7 activity, respectively. Caspase-3/7 activity was attenuated by 52% when cells were treated with a combination of EPA and DHA (P = .0034). Treatment with EPA alone, DHA alone, and the combination of EPA and DHA all resulted in equal attenuation of apoptotic mediator gene expression. CONCLUSIONS: The combination of EPA and DHA resulted in a synergistic attenuation of bile acid-induced hepatocellular apoptosis, as assessed by caspase-3/7 activity, compared to EPA and DHA separately. The combination of EPA and DHA did not result in a synergistic attenuation of the upregulation of Fas or TRAIL-R2. These data suggest that EPA and DHA may be working via multiple intracellular pathways to attenuate bile acid-induced apoptosis.

Enteral fish oil for treatment of parenteral nutrition-associated liver disease in six infants with short-bowel syndrome.

STUDY OBJECTIVE: To evaluate the use of enteral fish oil for the treatment of parenteral nutrition-associated liver disease (PNALD). DESIGN: Retrospective case series. SETTING: Pediatric academic hospital and outpatient clinic. PATIENTS: Six parenteral nutrition-dependent infants with short-bowel syndrome and PNALD. MEASUREMENTS AND MAIN RESULTS: The six infants received supplementation with enteral fish oil, and treatment was evaluated over a 12-week period. The PNALD, as reflected by elevated total bilirubin levels, completely reversed in four of the six infants within a mean ± SD of 5 ± 2.6 weeks (range 2-8 wks) after initiation of the enteral fish oil supplementation. In addition, improvement in enteral feedings occurred after starting enteral fish oil therapy. CONCLUSION: Enteral fish oil may be an effective adjunctive treatment option for infants with PNALD, particularly for those infants with PNALD who are tolerating some amount of enteral nutrition as the result of an adequate amount of small bowel.

Overexpression of apolipoprotein A-IV enhances lipid secretion in IPEC-1 cells by increasing chylomicron size.

Intestinal apolipoprotein A-IV expression is highly regulated by dietary lipid in newborn swine, suggesting a role in lipid absorption. Constitutive overexpression of apoA-IV in newborn swine enterocytes enhances basolateral secretion of triacylglycerol (TG) in TG-rich lipoproteins 4.9-fold (Lu, S., Yao, Y., Meng, S., Cheng, X., and Black, D. D. (2002) J. Biol. Chem. 277, 31929-31937). To investigate the mechanism of this enhancement, IPEC-1 cells were transfected with a tetracycline-regulatable expression system (Tet-On). In cells incubated with oleic acid, a dose response relationship was observed between medium doxycycline concentration and basolateral apoA-IV and TG secretion. Similarly regulated expression of apoA-I did not enhance lipid secretion. The mean diameter of TG-rich lipoproteins secreted from doxycycline-treated cells was larger than from untreated cells (87.0 nm versus 53.4 nm). Basolateral apoB secretion decreased. Using the same expression system, full-length human apoA-IV (376 amino acids); a "pig-like" human apoA-IV, lacking the C-terminal EQQQ repeats (361 amino acids); and a "chicken-like" apoA-IV, further truncated to 343 amino acids, were expressed in IPEC-1 cells. With increasing protein secretion, cells expressing the full-length human apoA-IV displayed a 2-fold increase in TG secretion; in sharp contrast, cells expressing the pig-like human apoA-IV displayed a 25-fold increase in TG secretion and a 27-fold increase in lipoprotein diameter. When human apoA-IV was further truncated to yield a chicken-like protein, TG secretion was inhibited. We conclude that overexpression of swine apoA-IV enhances basolateral TG secretion in a dose-dependent manner by increasing the size of secreted lipoproteins. These data suggest that the region in the human apoA-IV protein from residues 344 to 354 is critical to its ability to enhance lipid secretion, perhaps by enabling the packaging of additional core TG into chylomicron particles. The EQQQ-rich region may play an inhibitory or modulatory role in chylomicron packaging in humans.