lysosomal acid lipase activity in nonalcoholic fatty liver disease

Conditions: Non-Alcoholic Fatty Liver Disease

Summary: non-alcoholic fatty liver disease (nafld) is a multifactorial disease affecting a quarter of the world population. pathological accumulation of fat, into the hepatocytes, is the first hit and is due to altered hepatic and extrahepatic lipogenesis, lipolysis and lipophagy of the large lipid droplets. lipophagy plays a key role in the onset of nafld, in the autolysosomes, small droplets of fat are catabolized by lysosomal acid lipase (lal) enzyme which hydrolyzes cholesterol esters and triglycerides forming cholesterol and free fatty acids. our research group demonstrated that, subjects affected by nafld, present a reduced enzymatic activity either compared to patients with chronic liver disease of different etiology, but comparable staging, either compared to healthy control subjects. leukocytes are the main site of enzymatic activity in the blood, however, our research group has shown that it can also be detected inside the platelets, demonstrating how the lal activity can be exchanged between cells. furthermore, our group has shown, for the first time, how the intracellular enzymatic activity is reduced, independently of the platelets and leukocytes count and progressively from chronic liver disease up to cirrhosis. among factors which contribute to altered lipid metabolism, the genetic predisposition to the accumulation of hepatic fat must be counted. several variants of genes that code for proteins implicated in the digestion or storage of fats, are involved. in this study were considered: patatin-like phospholipase domain-containing 3 (pnpla3), transmembrane 6 superfamily 2 (tm6sf2) and 17β-hydroxysteroid dehydrogenase type 13 (hsd17b13). the rs738409 variant (c\> g, p.i148m) of the pnpla3 gene consists of a protein in which the catalytic site is not entirely accessible to the substrate which, consequently, accumulates in the storage site. this variant is commonly found in nafld subjects and it has been widely reported how the variant carriers progress faster towards severe disease (steatohepatitis) than wild type subjects. the tm6sf2 gene encodes a membrane transporter involved in the triglycerides movement, the rs58542926 (c\> t e167k) variant has been associated with an increased predisposition towards liver fibrosis in nafld subjects. this is likely due to the loss of protein function resulting in hepatic retention of triglycerides and cholesterol. unlike pnpla3 and tm6sf2, the rs72613567 (ta\> taa) variant of the hsd17b13 gene has a protective effect against nafld progression. it is characterized by a protein loss of function that protects against chronic liver damage and mitigates the progression of the disease although how the protective effect occurs is still under study. due to the multifactorial etiology of the disease, to the need of carrying out a targeted surveillance in predisposed genetic subjects and, in order to prevent nalfd progression towards severe pathological forms characterized by an increased mortality, in this study, 316 subjects will be enrolled. they will be divided as follows: italian caucasians, aged\> 18 and \ 18 and \<70 years, with non-cirrhotic nafld and carriers of the wild type allele. the following exclusion criteria will be considered: any type of malignant disease in the past 5 years, any type of inflammatory or autoimmune disease, corticosteroids for systemic use, any type of drug that may affect body weight or body composition, insufficiency kidney (gfr \ 140 g / week for men and 70 g / week for women), participation in a weight reduction program in the past 3 months, bile salts, cholestyramine in the last 6 months prior to enrollment, previous cholecystectomy, gallbladder disease. peripheral blood will be withdrawn in order to measure haematic lipids (total cholesterol and fractions, triglycerides), total blood lal activity, to perform genetic analysis and finally to evaluate lipase activity into the platelets. hepatic elastography will be also executed, in 100 patients, according to the presence/absence of the pnpla3 variant, in order to weigh up the genetic predisposition on nafld development or progression finally, in subjects who present a lipase activity 30% lower than the normal value (0.88 ± 0.38 (mean ± sd), the methylation of the lipa promoter will be studied.


Eligibility criteria:
inclusion criteria: * caucasian italian subjects * age \> 18 and \< 70 years * non-cirrhotic nafld exclusion criteria: * any malignant disease during the last 5 years * any inflammatory or autoimmune disease * corticosteroids for systemic use * any medication potentially affecting body weight or body composition * syndromic obesity * renal failure (gfr\<90 ml/min) * heart failure (nyha classes ii-iv) * any type liver disease rather than nafld * alcohol intake \>140g/ week for men and 70g/ week for women * participation in a reducing- weight program in the last 3 months * cholestyramine during the last 6 months before enrollment * previous cholecystectomy * gallbladder disease

Keywords: lysosomal acide lipase pnpla3 tm6sf2 hsd17b13 hepatic elastography