Furthermore, the low-frequency E167K variant of TM6SF2 and rare mutations in APOB, which impair very low-density lipoproteins secretion, predispose to progressive fatty liver.
Partial MTP inhibition using small molecule inhibitors, such as lomitapide, can effectively lower plasma low-density lipoprotein-cholesterol and apolipoprotein B levels, but is associated with gastrointestinal side effects and hepatic steatosis, whose long-term sequelae remain unclear; lomitapide has accordingly only been approved as a treatment for homozygous familial hypercholesterolemia.
We used exome sequencing to discover a novel nonsense mutation in exon 26 of APOB (p.K2240X) responsible for low cholesterol and fatty liver in a large kindred.
Familial hypobetalipoproteinaemia (FHBL) is a codominant disorder characterised by fatty liver and reduced plasma levels of low-density lipoprotein (LDL) and its protein constituent apolipoprotein B (apoB).
Moreover, very low-density lipoprotein (VLDL) subclass analysis showed that the VLDL2 fraction of the fatty liver subgroup contained significantly less cholesterol and triglycerides (P = .02 for both parameters), which was likely explained by a decreased VLDL2 particle number because VLDL2 apolipoprotein B levels tended to be lower (P = .08).
We conclude that hepatic steatosis in apoB/BATless mice is associated with elevated rates of hepatic lipogenesis that are linked directly to increased hepatic expression of PPARgamma2.
Fatty liver is frequent in the apolipoprotein B (apoB)-defective genetic form of familial hypobetalipoproteinemia (FHBL), but interindividual variability in liver fat is large.
Familial hypobetalipoproteinemia (FHBL) is a genetically heterogeneous condition characterized by very low apolipoprotein B (apoB) concentrations in plasma and/or low levels of LDL-cholesterol (LDL-C) with a propensity to developing fatty liver.
This study suggests that: i) fatty liver invariably develops in FHBL carriers of short and medium-size truncated apoBs (< apoB-48), but its occurrence needs additional environmental factors in carriers of longer apoB forms; ii) intestinal lipid malabsorption develops only in carriers of short truncated apoBs, which are not secreted into the plasma; and iii) cerebrovascular disease due to premature atherosclerosis may occur even in FHBL subjects.
Given that PCSK9 degrades the LDL receptor (LDLR) and prevents the removal of LDL from the blood into the liver, in the present study we examined the effect of hepatic steatosis on LDLR expression and circulating LDL cholesterol levels.
Here, we demonstrate that adenovirus-mediated overexpression of SIRT1 in the liver of diet-induced insulin-resistant low-density lipoprotein receptor-deficient mice and of genetically obese ob/ob mice attenuates hepatic steatosis and ameliorates systemic insulin resistance.
Primarily in female mice, hepatic cholesterol accumulation induced by SCP-2 overexpression was associated with increased levels of LDL-receptor, HDL-receptor scavenger receptor-B1 (SR-B1) (as well as PDZK1 and/or membrane-associated protein 17 kDa), SCP-2, liver fatty acid binding protein (L-FABP), and 3alpha-hydroxysteroid dehydrogenase, without alteration of other proteins involved in cholesterol uptake (caveolin), esterification (ACAT2), efflux (ATP binding cassette A-1 receptor, ABCG5/8, and apolipoprotein A1), or oxidation/transport of bile salts (cholesterol 7alpha-hydroxylase, sterol 27alpha-hydroxylase, Na(+)/taurocholate cotransporter, Oatp1a1, and Oatp1a4).