Keep database lookup in memory and get values in frequent
Some quick notes:


LUApplicationParams is not a good method name. It doesn't tell me what it does, and moreover it isn't even a verb.
m_LUApplicationParams isn't a good name for a field or property. I'm not a fan of the "m_" naming, it contains an obscure abbreviation or acronym (LU), and it doesn't tell me what it contains, which is especially bad considering this is a Dictionary&lt;string, Dictionary&lt;string, string&gt;&gt;.
I'd move all of the logic inside if (m_LUApplicationParams == null) to a separate method. I even wonder whether this would be the right place for such logic (although I have done such things myself).
blLU doesn't tell me anything, even when it is used like var blLU = new LU();.
Why do you do DataTable dt = new DataTable();? It's pointless since the next line assigns a value to dt anyway.
"LangId" is used three times. Suppose you ever need to change it: wouldn't it be handier if it were a constant?
dt.Rows[i]["LangId"].ToString() is used three times: then why not assign it to a variable?
GuidId is a parameter and thus should be CamelCase. But is GuidId even a proper name, considering that the other code suggests it is actually an id to identify the langhuage: "LangId"?
What does variable represent? Even the field name isn't helping, since that is "Variable" also. I'd hate to be the next person to maintain this code since obviously a lot of information is missing from it.
You do .FirstOrDefault() and then immediately use the .Value of the result; but what if there is no value? 
Also, .FirstOrDefault() suggests multiple values are possible, is that a possibility you want? And why would the first result be the correct one?
Why do you do .ToString() to the result of .FirstOrDefault().Value? Why do you fear that the value of a Dictionary&lt;string, string&gt; key-value pair wouldn't be a string?
You do .Where and then .FirstOrDefault: replace this by .FirstOrDefault(y =&gt; y.Key == variable).




If you need to fetch a specific value from a DataRow, why not extract such code to a method?

private string GetValue(DataRow row, string key)
{
    return row[key].ToString();
}




Avoid doing Dictionary.ContainsKey: if you need to use the value of said key, use Dictionary&lt;TKey, TValue&gt;.TryGetValue.

var row = dt.Rows[i];
var languageId = GetValue(row, "LangId");

Dictionary&lt;string,string&gt;() contentByVariable;
if(!m_LUApplicationParams.TryGetValue(languageId, out contentByVariable))
{
    contentByVariable = new Dictionary&lt;string,string&gt;();
}

contentByVariable.Add(GetValue(row, "Variable"), GetValue(row, "Content"));
m_LUApplicationParams[languageId] = contentByVariable;




But if I were you I'd rethink this entire logic. A Dictionary&lt;string, Dictionary&lt;string, string&gt;&gt; is ugly and unwieldy; IMHO the nested dictionary should be a custom class. 

I also feel this code is odd and possible buggy: data is retrieved for an applicationId yet this parameter is completely absent in m_LUApplicationParams. The GuidId that is passed is assumed to be present as a key in m_LUApplicationParams, same for the variable.